Peter Rogiers

Erythropoietin response is blunted in critically ill patients

Objectives: Critically ill patients often develop anaemia which can be related to a number of factors. However, the exact causes of anaemia in many patients remain unexplained. We hypothesized that the relationship between erythropoietin (EPO) and haematocrit may be altered in critically ill patients. Design: Serum concentrations of EPO were serially determined by the ELISA method in 36 critically ill, non-hypoxaemic patients who stayed more than 7 days in the Intensive Care Unit, including 22 patients with sepsis and 14 without. Eighteen ambulatory patients with iron-deficiency anaemia served as a control group. Setting: Two University Hospital Intensive Care Departments. Results: A significant inverse correlation between serum EPO and haematocrit levels was found in the control patients (r = −0.81, p < 0.001), but not in the critically ill patients (r = −0.09, NS), except in a subgroup of non-septic patients without renal failure (r = −0.61, p < 0.01). Conclusions: EPO levels can be inappropriately low in critically ill patients, so that EPO deficiency may contribute to the development of anaemia in these patients. This phenomenon is observed not only in the presence of acute renal failure, but also in the presence of sepsis.

Continuous venovenous hemofiltration improves cardiac performance by mechanisms other than tumor necrosis factor-α attenuation during endotoxic shock

OBJECTIVE To assess the effects of continuous venovenous hemofiltration (CWH) on global and regional hemodynamics, plasma lactate, and tumor necrosis factor-oa (TNF-a) levels during endotoxic shock in dogs. METHODS Thirty pentobarbital-anesthetized and mechanically ventilated dogs were divided into six groups of five dogs each. Group 1 served as a control, undergoing CWH at 3 Uhr without endotoxin. Group 2 served as the endotoxin-alone time-matching group. Group 3 received CWH 1 hr after endotoxin at 3 Uhr for 270 mins. Group 4 received CWH 1 hr after endotoxin at 3 Uhr for 150 mins and at 6 Uhr for an additional 120 mins. Group 5 and group 6 received the ultrafiltrate from group 1 and group 3, respectively. MEASUREMENTS AND MAIN RESULTS Three hours after endotoxin challenge, dogs treated with CWH at 3 Uhr had a higher cardiac output (4.9 + 0.6 vs. 2.9 + 0.6 Umin; p < .05) and stroke volume (35 + 7 vs. 20 + 4 mL; p < .05) and a lower pulmonary vascular resistance (116 26 vs. 331 + 126 dyne-sec/cm5; p < .05) than the endotoxin-alone group. Five hours after endotoxin, dogs treated with CWH at 6 Uhr also had higher hepatic (464 + 164 vs. 126 + 75 mUmin; p < .05) and femoral (95 + 46 vs. 30 + 34 mL/min; p < .05) blood flow. Moreover, dogs treated with CWH at 6 Uhr had higher mean arterial blood pressure (84 + 24 vs. 40 + 15 mm Hg; p < .05) and left ventricular stroke work index (1.1 + 0.6 vs. 0.2 + 0.2 g/kg; p < .05) than the endotoxin-alone group. Plasma lactate levels were lower in the CWH group at 6 Uhr (2.7 + 1.1 mmol/L) than in the endotoxin-alone group (4.4 + 0.6 mmol/L; p < .05). Plasma TNF-ao levels were unaffected, and only minor amounts of TNF-o were found in the ultrafiltrate. CONCLUSION In this acute endotoxic shock model, CWH at 3 Uhr improved cardiac performance and decreased pulmonary vasoconstriction. Moreover, CWH at 6 LUhr also increased arterial blood pressure and left ventricular stroke work, increased hepatic and femoral arterial blood flow, and decreased blood lactate levels. These effects were not attributable to TNF-alpha removal.

Effects of methylene blue on oxygen availability and regional blood flow during endotoxic shock

OBJECTIVE We hypothesized that methylene blue, by inhibiting the activation of soluble guanylate cyclase mediated by nitric oxide, may reverse systemic hypotension, enhance myocardial function, and improve peripheral distribution of blood flow during endotoxic shock. DESIGN Randomized, controlled, acute intervention study. SETTING University intensive care laboratory. SUBJECTS Twenty-one healthy, anesthetized, mongrel dogs, weighing 26 +/- 4 kg. INTERVENTIONS Groups 1 (n = 7) and 2 (n = 7) received endotoxin (2 mg/kg iv) alone combined with increasing doses of 2.5, 5, 10, and 20 mg/kg iv of methylene blue. Each dose was administrated for 30 mins with a free interval of 30 mins. Group 3 (n = 7) served as a control group, receiving the same doses of methylene blue in the absence of endotoxin. All animals were given normal saline to keep cardiac filling pressures constant. Blood flow probes were placed around the superior mesenteric, renal, and femoral arteries to measure regional blood flow by ultrasonic technique. Data were collected every 30 mins during the study. MEASUREMENTS AND MAIN RESULTS After endotoxemia, methylene blue increased systemic and pulmonary arterial pressure and vascular resistances in a dose-dependent manner up to 10 mg/kg, but had no effect on cardiac index. At the highest dose, methylene blue decreased arterial pressure and systemic vascular resistance. At doses of methylene blue of < or = 10 mg/kg, mesenteric and femoral blood artery flow increased. At the highest dose of 20 mg/kg, femoral artery blood flow further increased, but mesenteric blood flow decreased. Renal artery blood flow was unaffected by methylene blue. In the absence of endotoxin, methylene blue at doses of 2.5 or 5 mg/kg did not alter mean arterial pressure, but reduced cardiac index, indicating an increase in systemic vascular resistance. In contrast, the higher doses of 10 or 20 mg/kg of methylene blue decreased mean arterial pressure and systemic vascular resistance. However, pulmonary arterial pressure and pulmonary vascular resistance increased in a dose-dependent manner. Mesenteric and renal artery blood flow decreased but femoral blood flow increased. As in the presence of endotoxin, methylene blue induced dose-related increases in oxygen uptake and oxygen extraction ratio, but did not alter oxygen delivery. Methylene blue largely attenuated the endotoxin-induced increase in plasma nitrite concentrations. CONCLUSIONS Low and moderate doses of methylene blue can significantly increase arterial blood pressure but not cardiac index during endotoxic shock. Methylene blue infusion may selectively increase mesenteric blood flow. High doses of methylene blue can worsen systemic hypotension, myocardial depression, and pulmonary hypertension after endotoxemia.

Fever control in septic shock: beneficial or harmful?

The beneficial effects of interventions to control fever in sepsis are controversial. We investigated whether the use of acetaminophen and external cooling is beneficial to control fever in septic shock. We studied 24 fasted, anesthetized, invasively monitored, mechanically ventilated female sheep (27.0 ± 4.6 kg) that received 0.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Ringers lactate (RL) was titrated to maintain pulmonary artery occlusion pressure (PAOP) at baseline levels throughout the experimental period. During the 2 h after the surgical operation, animals were placed in the hypothermia group if their temperature fell below 36.0°C; the other animals were randomized to three groups: high fever (T > 39.0°C), mild fever (37.5°C < T < 38.5°C), and normothermia (36.0°C < T < 37.0°C). The administration of 25 mg/kg acetaminophen every 4 to 6 h combined with external cooling (ice pad) was used to control core temperature in these three groups. The PaO2/FiO2 ratio was higher and blood lactate concentration was lower in the high fever than in the other groups (P < 0.01 and 0.05, respectively). Survival time was longer in the high fever group (25.2 ± 3.0 h) than in the mild fever (17.7 ± 3.5 h), normothermia (16.0 ± 1.9 h), and hypothermia (18.5 ± 2.5 h) groups (P < 0.05 for all). Plasma heat shock protein (HSP) 70 levels were higher in the two fever groups than in the other groups (P < 0.05). In this clinically relevant septic shock model, the febrile response thus resulted in better respiratory function, lower blood lactate concentration, and prolonged survival time. Antipyretic interventions including acetaminophen and external cooling were associated with lower circulating HSP70 levels. These data challenge the temperature control practices often used routinely in acutely ill patients.

Effects of N-Acetyl-L-Cysteine on Regional Blood Flow during Endotoxic Shock

We previously reported that N-acetyl-L-cysteine (NAC), an oxygen free-radical scavenger, can increase the oxygen extraction capabilities during endotoxic shock when blood flow is progressively reduced. In the present study, we investigated whether the protective effects of NAC are related to an improvement in regional blood flow following endotoxemia. Fourteen anesthetized, saline-infused and ventilated dogs were divided into two groups: 7 dogs received NAC (150 mg/kg, followed by a 20 mg/kg.h infusion), and the other 7 dogs served as a control time-matching group. Thirty minutes later all the dogs received Escherichia coli endotoxin (2 mg/kg) i.v. A saline infusion was started 30 min after endotoxin challenge to restore pulmonary artery occlusion pressure to baseline and maintain it constant. Regional blood flow was measured by ultrasonic volume flowmeter. In the control group, arterial pressure, left ventricular stroke work index and systemic vascular resistance remained lower than baseline. Mesenteric, renal and femoral arterial blood flow increased but only femoral blood flow returned to baseline levels. In the NAC group, cardiac index and left ventricular stroke work index remained higher and systemic and pulmonary vascular resistance were lower than in the control group. Blood flow in mesenteric, renal and especially femoral arteries was higher than in the control group. Fractional blood flow increased only in the femoral artery. PaO2 and PvO2 had similar courses in the two groups. A higher venous admixture was associated with a higher cardiac index and a lower pulmonary vascular resistance in the NAC group. Oxygen delivery and oxygen-uptake were higher in the NAC-treated than in the control animals throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer's lactate-does it really make a difference?

The aim of this study was to investigate whether the type of i.v. fluid administered has an impact on outcome in an animal model of septic shock. The study included 28 anesthetized, invasively monitored, mechanically ventilated female sheep (29.5 ± 4.0 kg), which received 0.5 g/kg body weight of feces into the abdominal cavity to induce peritonitis. During the surgical operation and 4 h after feces spillage, only Ringers lactate (RL) was administered in all animals. Thereafter, animals were randomized to receive continuous infusions of RL (n = 7) alone or combined with either 20% albumin (n = 7, volume ratio to RL 1:10) or 6% hydroxyethyl starch (HES) (n = 7, volume ratio to RL 1:1), or gelatin alone (n= 7, no volume limitation). Fluid resuscitation was titrated to maintain pulmonary artery occlusion pressure at baseline levels throughout the experiment. No antibiotics or vasoactive drugs were administered, and animals were monitored until their spontaneous death. Hemodynamic variables were better with HES and albumin than with the other fluids, as reflected by higher stroke volume, cardiac index, and oxygen delivery (all P < 0.05). Hydroxyethyl-starch-treated animals also had lower arterial lactate concentrations (P < 0.01). However, times to develop hypotension and oliguria were similar in all groups. Blood interleukin (IL) 6 concentrations were significantly increased in all groups. The mean survival time was similar in all groups. In this clinically relevant model of prolonged septic shock, albumin and HES solution resulted in higher cardiac output, oxygen delivery, and lower blood lactate levels than gelatin and RL; however, the choice of i.v. fluid did not affect outcome.ABBREVIATIONS-RL-Ringers lactate; HES-Hydroxyethyl starch; PAOP-Pulmonary arterial occlusion pressure; IL-Interleukin; FiO2-Inspired oxygen fraction; PaO2-Arterial partial pressure of oxygen; PaCO2-Arterial partial pressure of carbon dioxide; MAP-Mean arterial pressure; CI-Cardiac index; DO2-Oxygen delivery; COP-Colloid osmotic pressure; ELISA-Enzyme-linked immunosorbent assay; PBS-Phosphate-buffered saline; HRP-Horseradish peroxidase; SD-Standard deviation; SE-Standard error; ANOVA-Analysis of variance

Optimal adrenergic support in septic shock due to peritonitis.

Background The authors evaluated optimal adrenergic support using norepinephrine, dopamine, and dobutamine in a clinically relevant model of septic shock. Methods Twenty-eight mature, female, anesthetized sheep (weight, 30.5 ± 3.6 kg) underwent cecal ligation and perforation and were randomized into four groups of seven animals to be treated with norepinephrine, dopamine-norepinephrine, dobutamine-norepinephrine, or no adrenergic agent. In all groups, lactated Ringers solution was administered to restore cardiac filling pressures to baseline. In the norepinephrine group, norepinephrine (0.5–5 &mgr;g · kg−1 · min−1) was titrated to maintain mean arterial pressure between 75–85 mmHg. In the dopamine-norepinephrine group, dopamine was given first, and norepinephrine was added only when mean arterial pressure remained below 75 mmHg despite the infusion of 20 &mgr;g · kg−1 · min−1 dopamine. In the dobutamine-norepinephrine group, dobutamine was started at the same time as norepinephrine and titrated up to 20 &mgr;g · kg−1 · min−1 to get a 15% increase in cardiac output. Results The dobutamine-norepinephrine group had greater cardiac output; superior mesenteric blood flow, oxygen delivery (Do2), and oxygen consumption (&OV0312;o2); and lower blood lactate concentration and partial pressure of carbon dioxide (Pco2) gap than the controls did. Cumulative urine output was significantly higher in the dobutamine-norepinephrine group than in the other groups. Survival time was significantly longer in the dobutamine-norepinephrine (24 ± 4 h), dopamine- norepinephrine (24 ± 6 h), and norepinephrine (20 ± 1 h) groups than the control group (17 ± 2 h;P < 0.05 vs. other groups), and significantly longer in the combined dopamine-norepinephrine and dobutamine-norepinephrine groups (24 ± 5 h) than in the norepinephrine alone group (P < 0.05). Histologic examination of lung biopsies revealed less severe lesions in the dobutamine-norepinephrine group than in the control and norepinephrine alone groups. Anatomic alterations in the lung, liver, and small intestine were less severe in the dobutamine-norepinephrine group than in the other groups. Conclusions In this prolonged septic shock model, association of norepinephrine with either dopamine or dobutamine resulted in the longest survival and the least severe pulmonary lesions. The combination of dobutamine with norepinephrine was associated with a better myocardial performance, greater Do2 and &OV0312;o2, lower blood lactate concentration and Pco2 gap, and less anatomic injury.

Beneficial effects of recombinant human activated protein C in a ewe model of septic shock.

Objective:To investigate the effects of activated protein C (APC) in a clinically relevant animal model of septic shock. Design:Prospective, randomized, controlled study. Setting:University medical center research laboratory. Subjects:Eighteen female sheep (body weight, 27–35 kg). Interventions:Animals were fasted, anesthetized, invasively monitored, and mechanically ventilated before receiving 0.5 g/kg body weight of feces intraperitoneally to induce sepsis. Fluid resuscitation with Ringer lactate was titrated to maintain pulmonary artery occlusion pressure at baseline levels. No vasoactive agents or antibiotics were used. Two hours after the induction of sepsis, animals were randomized to receive an infusion of APC (24 &mgr;g·kg−1·hr−1, n = 9) or an equivalent volume of vehicle (n = 9) throughout the experimental period. Measurements and Main Results:The APC-treated animals had significantly higher arterial pressure, urine output, Pao2/Fio2 ratios, and thoracopulmonary compliance than the control animals. They had lower pulmonary arterial pressure and arterial lactate concentrations than the control animals. Plasma colloid oncotic pressure was better maintained in the APC-treated group than in the control group (p < .05). Prothrombin time and activated partial thromboplastin time were altered less, and plasma D-dimer concentrations were significantly lower in the APC-treated group than in the control group (p < .05). The blood protein C concentration and platelet count were maintained better in the APC-treated group than in the control group (p < .05). APC administration was associated with significantly longer survival (median, 27 hrs vs. 20 hrs; p < .05). At postmortem examination, the lung wet/dry ratio was significantly lower in the APC group than in the control group (6.3 ± 0.7 vs. 7.1 ± 1.2, p < .05). Conclusions:In this clinically relevant model of septic shock due to fecal peritonitis, administration of APC had beneficial effects on hemodynamic variables, gas exchange, lactic acidosis, and coagulation abnormalities. Higher colloid oncotic pressures and lower lung wet/dry ratios at autopsy suggest preserved endothelial integrity. APC administration resulted in prolonged survival.

A REGISTRY OF PATIENTS TREATED WITH DROTRECOGIN ALFA (ACTIVATED) IN BELGIAN INTENSIVE CARE UNITS - AN OBSERVATIONAL STUDY

Abstract Background: Drotrecogin alfa (activated) [DrotAA] is the only specific sepsis therapy that has been shown to reduce mortality. The objectives of this study were to document the profile of patients treated with DrotAA in Belgian intensive care units (ICUs), using data from a database established as part of drug reimbursement conditions in Belgium, and to compare the observed hospital mortality of these patients with their expected mortality, calculated using data from non-DrotAA-treated patients from the Belgian section of PROGRESS, a separate, voluntary, international sepsis registry collecting data from patients with severe sepsis. Material and methods: Data from the non- DrotAA-treated patients in PROGRESS were used to calculate the expected mortality rates for DrotAA-treated patients in the Belgian registry. Using a logistic regression equation, these rates were controlled for age and the presence or absence of organ dysfunction in each of 5 organ systems. The same logistic regression technique was used to control the mortality rates observed in the DrotAAtreated patients from the Belgian registry for age and the presence or absence of each of the 5 organ dysfunctions. Adjusted expected and observed hospital mortality rates could then be compared. Results: There were 436 DrotAA patients in the Belgian registry. Almost all the patients (99.5%) had at least 2 organ failures and the hospital mortality was 51.6%. Two hundred and eighty-six of the patients had enough baseline data to be included in the regression model. Using data from the PROGRESS non-DrotAA patients, the predicted hospital mortality, controlled for age and organ dysfunction, of Belgian registry patients, had they not been treated with DrotAA, was 63.5%. The observed hospital mortality, again controlled for age and organ dysfunction, of the 286 Belgian registry patients was 50.7%, implying an adjusted absolute mortality reduction of 12.8%. Conclusions: Comparing Belgian reimbursement registry data with those of a voluntary severe sepsis register provides support for the observation that DrotAA reduces mortality rates in severe sepsis and septic shock.

Blood Warming during Hemofiltration Can Improve Hemodynamics and Outcome in Ovine Septic Shock

Background:This study was designed to evaluate the effects of blood warming during hemofiltration on global and regional hemodynamics, plasma lactate, and 24-h survival during septic shock. Methods:Twenty anesthetized and mechanically ventilated sheep underwent induction of peritonitis and, 4 h later, were treated by hemofiltration with (n = 10) or without (n = 10) blood warming. Results:In the group without blood warming, body temperature decreased after starting hemofiltration and remained below baseline. In the other animals, body temperature stabilized at baseline level during hemofiltration and increased to a maximum of 40.8°C thereafter. The group without warming experienced a decrease in blood pressure (from 90 mmHg to 38 mmHg) and cardiac output (from 4.0 l/min to 2.3 l/min). Metabolic acidosis and the increase in lactate were less marked when temperature was maintained. None of the animals without warming but all of the animals with warming survived to 16 h. Conclusions:Differences in temperature during hemofiltration resulted in striking differences in hemodynamics, metabolic acidosis, and survival rate in this clinically relevant experimental model of septic shock.