J W Fijen

Leukocyte activation and cytokine production during experimental human endotoxemia

Background: At present, it is unclear whether in experimental endotoxemia, the pro-inflammatory response observed in healthy volunteers is followed by an anti-inflammatory response, as observed in patients with sepsis. We studied the evolution of a number of inflammatory parameters during a prolonged period (24 h) after infusion of endotoxin in healthy subjects. Methods: Six healthy male subjects received an infusion of endotoxin (4 ng/kg body weight). Blood was drawn before, and at various intervals up to and including 24 h after, endotoxin infusion. Circulating cytokine levels, leukocyte activation surface markers, plasma lactoferrin, and neopterin levels were measured, and clinical signs and symptoms were noted during a 24-h period. Monocyte and neutrophil activation after endotoxin infusion is investigated in relation to the inflammatory response. The extent of neutrophil and monocyte activation was correlated to clinical markers and blood levels of inflammatory mediators and cytokines. Results: Tumor necrosis factor-alpha appeared 30 min after infusion in the circulation, peaking (5665+/-1910 pg/ml) at 2 h. Interleukin-10 appeared 60 min after infusion, peaking (427+/-348 pg/ml) at 3 h. The expression of leukocyte activation markers increased significantly after infusion. Expression of HLA-DR on monocytes decreased significantly after 3 h (P=0.03). There was a correlation between the TNF-alpha:IL-10 ratio and the CD11b:HLA-DR ratio (P=0.03). Conclusions: During experimental human endotoxemia, an initial pro-inflammatory response is successfully compensated by an anti-inflammatory response, leading to homeostasis. This is in contrast to what happens in septic patients with compensatory anti-inflammatory response syndrome. The inflammatory balance, expressed as the cytokine pro:anti-inflammatory ratio, is reflected at a cellular level.

Monocyte intracellular cytokine production during human endotoxaemia with or without a second in vitro LPS challenge: effect of RWJ-67657, a p38 MAP-kinase inhibitor, on LPS-hyporesponsiveness

In the present study, we investigated the effect of RWJ‐67657, a p38 MAP kinase inhibitor, upon in vivo LPS‐induced monocyte cytokine production and upon monocyte LPS‐hyporesponsiveness. Thirty minutes before a single injection of LPS (4 ng/kg BW), healthy male volunteers received a single oral dose of RWJ‐67657 at increasing dosages (0–1400 mg). Blood samples (pre‐medication, 3, 6 and 24 h after LPS) were immediately incubated with LPS (reflecting LPS‐hyporesponsiveness) or without LPS (reflecting in vivo monocyte stimulation) for 4 h at 37°C. Following red blood cells lysis and white blood cell permeabilization, cells were labelled with α‐CD14‐FITC and α‐IL‐1β, α‐IL‐12 or α‐TNFα (PE‐labelled), fixed, and analysed using flow cytometry. In vivo LPS injection resulted in an increased percentage of circulating monocytes producing IL‐1β, TNFα and IL‐12 only at 3 h after the LPS injection. This was dose‐dependently inhibited by RWJ‐67657 treatment. LPS‐hyporesponsiveness to in vitro LPS treatment was most prominent at 3 and 6 h after the in vivo LPS injection; compared with pre‐medication monocytes, at these intervals a reduced percentage of monocytes produced IL‐1β, TNFα or IL‐12 after the in vitro LPS stimulus. At t = 6 h, this LPS‐hyporesponsiveness could dose‐dependently be inhibited by RWJ‐67657 treatment of the volunteers. We therefore conclude that p38 MAP kinase inhibition with RWJ‐67657 inhibited monocyte production of cytokines following in vivo LPS injection. Treatment with RWJ‐67657 also reversed the LPS‐hyporesponsiveness. Whether this result can be extended to the clinical situation remains to be elucidated. Patients with sepsis or an otherwise high risk for multi‐organ failure are potential study groups.

Antidepressants self-poisoning and ICU admissions in a University Hospital in the Netherlands

Objectives: Many overdosed patients are admitted to an ICU. Antidepressants are frequently used. We examined clinical end-points of toxicity recorded during admission to our ICU of all antidepressants used in overdose. Design: Single centre; retrospective analysis, 5 consecutive years (1994 – 1998). Setting: Intensive and Respiratory Care Unit, Groningen University Hospital. Participants: 86 patients admitted to the ICU because of antidepressant self-poisoning — database of 258 consecutively admitted patients with (auto-) intoxication. Results: Significantly more patients were intoxicated with TCAs (65) compared with SSRIs (20; p < 0.05), despite the fact that the number of prescriptions of antidepressants in the community was greater for SSRIs than for TCAs. Patients intoxicated with TCAs needed significantly more often tracheal intubation (27/65 vs 7/20; p < 0.05), and these individuals had also significantly more often tachycardia (14 vs. 3) and QRS-complex widening (19 vs. 1), compared to those with non-TCA antidepressant intoxication (p < 0.05). Conclusions: TCA self-poisoning has remained the predominant cause of morbidity among patients with auto-intoxication admitted to our ICU in the previous years. The data from this ICU-population confirm previous evidence that SSRIs are safer in overdose than TCAs. This finding was not explained by more prescriptions in the community of TCAs compared with SSRIs. Physicians should be more reluctant in prescribing TCAs to depressed patients in whom the risk of self-poisoning is difficult to assess.

The Influence of Tumor Necrosis Factor–α and Interleukin-10 Gene Promoter Polymorphism on the Inflammatory Response in Experimental Human Endotoxemia

In this study, we show that there is no correlation between tumor necrosis factor-alpha gene promoter polymorphism at position -308, interleukin-10 gene promoter polymorphism at position -1082, and the cytokine levels they produce in the human endotoxemia model.

Pharmacokinetics of cefpirome in critically ill patients with renal failure treated by continuous veno-venous hemofiltration

Objective: To study the cefpirome pharmacokinetics of patients with sepsis and multiple organ failure treated with CVVH. Design: Measurements of serum and ultrafiltrate (UF) concentrations and in vitro sensitivity testing of isolated micro-organisms. Setting: University hospital-based, single ICU. Patients: Six critically ill CVVH- dependent patients with sepsis and multiple organ dysfunction syndrome in need of antimicrobial therapy. Age range: 60–75 years; APACHE II score for severity of illness on admission: 19–30. One patient survived. Interventions: Cefpirome i. v. was started at 2 g in 30 min, then continued 1 g i. v. b. i. d. Measurements: The UF rate was 27 ± 7 ml/min on day 1 and 34 ± 2 ml/min on day 2. Serum and ultrafiltrate samples were measured by a validated high performance liquid chromatography assay. Volume of distribution: 23 · 5(SD ± 4 · 6) l. Total cefpirome clearance was 32 ± 6 · 3 ml/min; cefpirome CVVH clearance (ClCVVH): 17 ± 4.2 ml/min; mean serum half-life (t1/2): 8.8 ± 2.3 h; mass transfer on day 1: 660 ± 123 mg/12 h (33 ± 6 % of administered dose)and day 2: 642 ± 66 mg/12 h (64 ± 7 %). Estimated sieving coefficient (ClCVVH/UF rate): 64 ± 11 %. In vitro sensitivity of isolated microbes was excellent except for two non-sensitive enterococci and Candida spp. Conclusions: The sieving coefficient (64 %) indicates that a substantial fraction of the drug is not filtered; clearance by pathways other than CVVH mounted to 50 % of the total clearance and increased on day 2, indicating that the dosing schedule used is appropriate for this setting. Cefpirome appeared to be safe in these patients and effective for most of the nosocomial microbial isolates. During more than 90 % of the time, serum levels were maintained above killing concentrations for susceptible micro-organisms.

Prone position in a spontaneously breathing near-drowning patient

Sir: In 1977 Douglas et al. [1] first observed improvement in arterial oxygen tension (PaO2) by prone positioning that prevented the need for mechanical ventilation in a patient with acute lung injury. Now, we describe a second case with moderate respiratory insufficiency where managing the spontaneously breathing patient in the prone position avoided the need for endotracheal intubation and mechanical ventilation. A 16-year-old boy with a history of epilepsy was admitted to hospital with acute, moderate respiratory insufficiency resulting from near drowning after a generalized seizure. On examination his temperature was 37.5 C and blood pressure 130/ 80 mmHg. He was slightly confused, there were spontaneous movements of the extremities and idiomuscular reflexes were present. Cardiac and abdominal examination revealed no specific abnormalities. He presented with tachypnea and mild cough and produced frothy blood-tinged sputum. His respiration rate varied between 30 and 40 breaths/min. Oxygen was applied through a face mask [approximate fractional inspired oxygen (FIO2) of 0.40]. On auscultation, crackles were noted over the left lung. Moderate respiratory insufficiency was based on the clinical symptoms and the PaO2/FIO2 was 31 kPa (233 mmHg). In order to improve gas exchange and reduce the work of breathing in our patient, we considered continuous positive airway pressure by face mask, but we first tried the prone position. The positional change was well tolerated and resulted in a remarkable clinical recovery with improved oxygenation: PaO2 rose from 12.5 to 22 kPa, arterial carbondioxide tension from 5.7 to 6.0 kPa, and the alveolar-arterial oxygen difference changed from 17.8 kPa (134 mmHg) to 4.1 kPa (33.2 mmHg) within 2 h. As a result, the high fractional inspired oxygen was tapered down. Chest radiograph in the supine position showed left unilateral consolidations (Fig.1a). On the chest radiographs (taken in the supine position) after 3 and 20 h of prone position, the pulmonary abnormalities had resolved (Figs.1b and 1c). The patient made an uneventful recovery, mechanical ventilation was redundant and he was discharged from hospital on day 4. While there seems to be little doubt of the beneficial effects of prone position on oxygenation in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS) [2,3], it remains unclear whether the same holds true in moderate respiratory insufficiency. In our patient, prone positioning rapidly reversed hypoxemia and prevented the necessity of orotracheal intubation and mechanical ventilation. Prone position alters the transpulmonary pressure in the atelectatic dorsal lung regions with a reduction in VA/Q mismatch and shunt [4]. The observed improvement in the alveolar-arterial oxygen difference coincided with favorable changes in radiographic appearance when the patient was turned from the supine to the prone position. Whether the changes in transpulmonary pressure due to maneuvering the body position of our patient are of an order of magnitude sufficient to open consolidated pulmonary units has often been suggested but is still questioned [5]. Perhaps the overall improvement in aeration observed in our patient is an additive Intensive Care Med (1999) 25: 1469±1478 Ó Springer-Verlag 1999 CORRESPONDENCE

Diffuse pulmonary infiltrates in immunocompromised patients

The differential diagnosis of bilateral interstitial pulmonary infiltrates in immunocompromised patients is very extensive. We describe two immunocompromised patients with diffuse pulmonary infiltrative changes. Bronchoscopic bronchoalveolar lavage after orotracheal intubation using topical anaesthesia combined with mild sedation in an ICU setting is safe in critically ill patients and often yields a conclusive diagnosis.