Joke Nollet

Remifentanil Directly Activates Human N-methyl-D- aspartate Receptors Expressed in Xenopus laevis Oocytes

Background: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva® (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-d-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva® directly stimulates human NMDA receptors. Methods: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. Results: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nm–1 mm each) or Ultiva® (0.01 pm–0.1 mm) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 μM/12 μM for glutamate/glycine and 3.5 nM for Ultiva®, and NR1A/2B EC50 values were 3.9 μM/1.9 μM for glutamate/glycine and 0.82 μM for Ultiva®. Glycine in combination with Ultiva® showed no additive effect compared with Ultiva® alone. Ultiva®-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 μM) did not stimulate NMDA receptors. Conclusion: These data indicate that Ultiva® but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.

Outcome in critically ill patients with allogeneic BM or peripheral haematopoietic SCT: a single-centre experience.

Outcome in haematological patients who develop critical illness has significantly improved over the last two decades, but less so in allogeneic BMT recipients. We prospectively investigated the outcome of 44 haematological patients with allogeneic BM or haematopoietic SCT (ABMT/AHSCT) requiring admission to the intensive care unit (ICU) of Ghent University Hospital between January 2000 and December 2007. We related outcome to the cause of critical illness, which was categorized as documented or clinically suspected bacterial infection, non-bacterial infection and non-infectious disease. Mechanical ventilation was required in 32 patients, and 12 patients received renal replacement therapy. Overall ICU-mortality, in-hospital mortality and 6-month mortality rates were 61, 75 and 80%, respectively. Hospital mortality rates in patients with bacterial infection (n=14), non-bacterial infection (n=13) and non-infectious disease (n=17) were 43, 85 and 94% (P=0.003). After adjustment for severity of illness sequential organ failure assessment (SOFA) score, bacterial infection (odds ratio 0.06, 0.01–0.36, P=0.002) was associated with significantly lower odds for hospital mortality. On the basis of our experience, ICU referral of ABMT/AHSCT patients is justifiable, as an acceptable fraction of these patients have longer-term survival. Documented or clinically suspected bacterial infection as the cause of critical illness is associated with better prognosis in comparison with other causes.

Fatal Acute Pulmonary Injury Associated with Everolimus

Objective: To report a case of fatal alveolar hemorrhage associated with the use of everolimus in a patient who underwent a solid organ transplant. Case Summary: In a 71-year-old cardiac transplant patient, ciclosporine was replaced with everolimus because of worsening renal function. Over the following weeks, the patient developed nonproductive cough and increasing dyspnea. His condition deteriorated to acute respiratory failure with hemoptysis, requiring hospital admission. Bilateral patchy alveolar infiltrates were apparent on chest X-ray and computed tomography. Cardiac failure was ruled out and empiric antimicrobial therapy was initiated. Additional extensive workup could not document opportunistic infection. Everolimus was discontinued and high-dose corticosteroid therapy was initiated. Despite this, the patient required invasive mechanical ventilation and died because of refractory massive hemoptysis. Autopsy revealed diffuse alveolar hemorrhage. Discussion: Everolimus is a mammalian target of rapamycin inhibitor approved for use as an immunosuppressant and antineoplastic agent. Its main advantage over calcineurin inhibitors (tacrolimus and cyclosporine) is a distinct safety profile. Although it has become clear that everolimus induces pulmonary toxicity more frequently than initially thought, most published cases thus far represented mild and reversible disease, and none was fatal. Here, we report a case of pulmonary toxicity developing over weeks following the introduction of everolimus, in which a fatal outcome could not be prevented by drug withdrawal and corticosteroid treatment. The association of everolimus and this syndrome was probable according to the Naranjo probability scale. Conclusions: This case indicates that with the increasing use of everolimus, clinicians should be aware of the rare, but life-threatening manifestation of pulmonary toxicity.

Bupivacaine inhibits thromboxane A2-Induced vasoconstriction in rat thoracic aorta

Plasma levels of thromboxane A2 (TXA2), an inflammatory mediator inducing platelet aggregation, bronchoconstriction, and vasoconstriction, are increased in the peri-operative period. A major role in the pathogenesis of perioperative thromboembolic and ischemic syndromes is attributed to this prostanoid. Local anesthetics (LA) inhibitsignalingofTXA2 receptorsexpressedincellmodels. Therefore, we hypothesized that LA may inhibit vasoconstriction induced by the TXA2 analog U46619 in rat thoracic aorta. Rings (3-mm length) of the rat thoracic aorta were mounted in organ baths and isometric contractile force was measured. Rings, with or without endothelium, were incubated for 60 min in bupivacaine (10−6 or 10−5 M)orKrebs-Henseleitsolution(controlgroup)andsubsequently exposed to cumulative concentrations of U46619 (10−10 to 10−6 M). The reversibility of the TXA2-induced vasoconstriction by bupivacaine was also studied. Pre-treatment of rings with bupivacaine concentration-dependently diminished TXA2-induced contraction in rat aortic rings. We found no significant differences in relaxing effect of bupivacaine between rings with and without endothelium. Contraction in rings established with U46619 could not be reversed by cumulative concentrations of bupivacaine. Bupivacaine inhibited carbachol-induced vascular relaxation. This study provides experimental evidence that bupivacaine is an endothelium-independent inhibitor of TXA2-induced vasoconstriction of rat thoracic aorta.

Early recognition of malignant lactic acidosis in clinical practice: report on 6 patients with haematological malignancies

Abstract Background: Malignant lactic acidosis is a potentially overlooked but life-threatening complication in patients with haematological malignancies. The aim of this study is to describe the features of six patients with malignant lactic acidosis and to discuss how its initial presentation can be differentiated from that of severe sepsis. Methods: We prospectively collected data of all consecutive patients with haematological malignancies, admitted to the Ghent University Hospital Intensive Care Unit (ICU) between 2000 and 2007. Results: Of 372 patients with haematological malignancies admitted to the ICU for life- threatening complications, 58 presented with lactic acid levels ≥ 5 mmol/L. Six were diagnosed with malignant lactic acidosis. All patients with malignant lactic acidosis had high-grade lymphoblastic malignancies and were referred with a tentative diagnosis of severe sepsis or septic shock; lactic acid levels exceeded 9.45 mmol/L and lactate dehydrogenase (LDH) levels were at least 1785 U/L. Two patients had hypoglycaemia. All had a pronounced polypnea. In all patients hepatic malignant involvement was suspected. Two of the six patients survived their episode thanks to the early recognition of malignant lactic acidosis and the prompt administration of chemotherapy. One patient was still alive 6 months after initiating chemotherapy. Conclusion: Malignant lactic acidosis is a rare and often rapidly fatal metabolic complication if not promptly recognized and treated. An elevated lactic acid concentration, in disproportion with the level of tissue hypoxia, together with high serum LDH are cornerstones in the diagnosis. In contrast to septic shock patients, pronounced polypnea (Kussmaul’s breathing pattern) rather than the haemodynamic instability is prominent.

ASPIRATION PNEUMONIA: AN UNDERESTIMATED CAUSE OF SEVERE RESPIRATORY FAILURE IN PATIENTS WITH HAEMATOLOGICAL MALIGNANCIES AND SEVERE ORAL MUCOSITIS?

Abstract Aspiration pneumonia is rarely considered in the differential diagnosis of respiratory failure in patients suffering from haematologic malignancies in daily practice. We describe four patients who were admitted with severe respiratory failure in the ICU over a one-year-period prospective survey (a total of 72 patients with haematological malignancies of which 34 presented with respiratory failure). All of these patients had chemotherapy-induced severe oral mucositis (WHO grade III-IV) for which three of them received opioids. All had a history of cough after oral rinsing and two of them experienced sudden brief desaturation in the days before ICU referral. Two of these patients, both in allogeneic bone marrow transplant setting, died. With this data, we want to draw the attention to the diagnosis of aspiration pneumonia in this group of patients.