J. E. Tulleken

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.

Hormones in the critically ill patient: to intervene or not to intervene?

Abstract. Critically ill patients show a variety of hormonal changes that appear to differ considerably in acute and prolonged critical illness. Whether these endocrine alterations serve as physiological adaptation or contribute to further deterioration remains an intriguing question. We review the recent literature and discuss whether measuring circulating hormone concentrations, performing stimulation tests, and intervening with hormone substitution could contribute to the recovery of critically ill patients.

Constrictive pericarditis after high-dose chemotherapy

High-dose chemotherapy with autologous stem-cell support for the adjuvant treatment of breast cancer and metastatic breast cancer has become common. This approach may offer a survival advantage over standard-dose therapy in women with earlier stage disease and in those who respond to pretransplant chemotherapy. We describe a patient who developed life-threatening constrictive pericarditis 8 weeks after high-dose chemotherapy. A 52-year-old woman presented with progressive dyspnoea and fatigue. Her past history revealed a mastectomy plus lymph-node dissection for breast cancer. Thereafter she participated in a trial comparing high-dose with standarddose chemotherapy as adjuvant treatment for breast cancer patients with four or more positive axillary lymph nodes. Treatment consisted of four courses of fluorouracil 500 mg/m, epirubicin 90 mg/m, and cyclophosphamide 500 mg/m daily every 3 weeks, followed by high-dose chemotherapy with cyclophosphamide (6 g/m), carboplatin (1600 mg/m), and thiotepa (480 mg/m) (CTC regimen) divided over 4 days. On day 7, peripheral stem-cell reinfusion was administered. 2 months after CTC a pericardial effusion developed without signs of tamponade. Transthoracic echocardiogram showed normal right and left ventricular function and a pericardial effusion of 2 cm but no evidence of right ventricular inflow limitation. No increase in viral antibody titres was noted and cultures taken from the blood, sputum, and urine were negative. The symptomless pericardial effusion was ascribed to the use of cyclophosphamide and consequently no pericardial tap was done. She was treated with furosemide. Short term followup was uneventful. After 2 weeks she was admitted because of exertional dyspnoea. Distended neck veins, pulsus paradoxus of 30 mm Hg, a decrease voltage in the electrocardiogram, and liver function disturbances were found. Transthoracic echocardiogram suggested normal left and right ventricular function and in particular no pericardial effusion. Swan-Ganz catheterisation showed, however, equalisation of right and left ventricular filling pressures compatible with constrictive pericarditis. She had a midsternal thoracotomy. Dense pericardial adhesions were seen at the right ventricular entry and pericardial stripping was performed. Cardiac performance strongly improved after surgery. Histologically, the surgical specimen revealed pericardial thickening due to proliferation of myofibroblasts. Specimens of pleural fluid and pericardial tissue were examined for microorganisms including mycobacteria, fungi, and viruses; all direct stains and cultures were negative. In addition, there was no evidence of connective-tissue diseases, mechanical trauma, myocardial infarction, or infiltration with malignant cells. The patient’s condition improved; 2 weeks later she was discharged in an excellent cardiopulmonary condition. After 3 months she fully resumed her domestic duties and job. Our patient developed a life-threatening but potentially reversible complication within 3 months of high-dose chemotherapy. The cause of this constrictive pericarditis was not established but it may be associated with high-dose chemotherapy. The CTC regimen is the most frequently used high-dose treatment schedule for breast cancer. When more frequent causes of dyspnoea such as pleural effusion, left ventricular failure, and malignancy have been excluded the clinician should be alerted to this potential complication of high-dose chemotherapy. 1 Gradishar WJ, Tallman MS, Abrams JS. High-dose chemotherapy for breast cancer. Ann Intern Med 1996; 125: 599–604. 2 Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol 1997; 15: 1870–79. 3 de Vries EGE, ten Vergert EM, Mastenbroek CG, Dalieso O, Rodenhuis S. Breast cancer studies in the Netherlands. Lancet 1996; 348: 407–08. 4 Braverman AC, Antin JH, Plappert MT, Cook EF, Lee RT. Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens. J Clin Oncol 1991; 9: 1215–23.

Condition on arrival of transferred critically ill patients

We performed a retrospective inventory of the condition of transferred patients to our 11-bed medical ICU, aimed firstly to measure the quality of these transports and secondly to identify variables that may predict a high risk of deterioration during transferral. By a search in our hospital database, we identified 112 consecutive patients (47 women/65 men) transferred from other hospitals (distance 20-350 km) to our ICU over a period of 14 months. The following data were collected on departure (if available) and on arrival: blood pressure, heart rate, temperature, oxygen saturation, routine laboratory parameters, arterial blood gas analysis, lactic acid, settings of mechanical ventilation, use of vasopressor/inotropic medication, presence of venous and arterial catheters and Apache II score on arrival. No major worsening during transportation was found, looking at the whole group. However, individual data showed severe deterioration of some patients during transport. We were not able to point out parameters that could predict hemodynamic or respiratory instability during transport or condition on arrival. In conclusion, quality of transport seems fairly good; in individual cases, improvements are possible. Therefore, we plan to investigate whether or not a strict protocol, based on recommendations in the literature and on local feasibility can further improve condition on arrival and survival of transferred ICU patients in our adherence region.

ACUTE LIVER FAILURE : THE HEART MAY BE THE MATTER

Abstract Hypoxic hepatitis secondary to heart failure is a known and treatable cause of liver failure. The diagnosis may be difficult, especially when symptoms of heart failure are absent. We present two patients who were transferred to our hospital with the diagnosis of acute liver failure to be screened for a liver transplantation. Both patients had increased serum levels of aminotransferases, lactic acidosis, coagulation disorders, and non-specific clinical symptoms. Echocardiography revealed right ventricular dysfunction. Treatment with inotropes resulted in a fast normalization of liver enzymes, acidosis and coagulation, confirming the diagnosis hypoxic hepatitis. In conclusion, when the cause of acute liver dysfunction is unclear, hypoxic hepatitis due to heart failure should be considered and echocardiography should be performed, even when symptoms are non-specific for heart failure.

Lessons from an unusual case: malignancy associated hypercalcemia, pancreatitis and respiratory failure due to ARDS

A 37-year old woman, presenting with severe hypercalcaemia-associated pancreatitis with pseudocyst formation, was admitted to intensive care because she developed ARDS with respiratory failure. Skeletal metastasis from non-small cell bronchial carcinoma were subsequently diagnosed. After she developed arterial occlusion in the lower limb, supportive treatment was withdrawn. Severe pancreatitis is an exceedingly unusual presentation of non-small cell bronchial carcinoma. Concepts of diagnostic and therapeutic strategies in the context of suspected unusual pathology, and the concept of futility are briefly discussed.

Post mortem examination in the intensive care unit: still useful?

cardial infarction, pulmonary embolus, and mesenteric thrombosis may be epiphenomena of the dying process. It is not easy to imagine how we can adapt our diagnostic process to prevent missing these diagnoses. We must also bear in mind that only diagnoses with a macroor microscopic substrate can be detected by PME. It is often disappointing how little substrate is found in patients who died of multiorgan failure or septic shock. The difficulty of translating PME findings in clinical practice and the lack of an answer to important questions are probably the most important reasons for the decline in PME rates. As a result the other important goals of PME, the educational and training aspects, can no longer be met. It is, important, for instance, for ICU personnel to see and feel an ARDS lung or a lung with emphysema. It improves the understanding of the ventilation problems during the ICU stay. It is also important in a training process that the person sees with his own eyes (autopsy) that the diagnosis was correct. In our view the emphasis must be on the educational aspects of PME instead of on finding the cause of death and searching for missed diagnoses. Otherwise we lose an educational tool due to the often disappointing answers it gives to other questions. It is therefore of ultimate importance that physicians in training attend the PME of the patients whom they treated.