Sepsis remains a major cause of morbidity and mortality mainly because of sepsis-induced multiple organ dysfunction. In contrast to preclinical studies, most clinical trials of promising new treatment strategies for sepsis have failed to demonstrate efficacy. Although many reasons could account for this discrepancy, the misinterpretation of preclinical data obtained from experimental studies and especially the use of animal models that do not adequately mimic human sepsis may have been contributing factors. In this review, the potentials and limitations of various animal models of sepsis are discussed to clarify to which extent these findings are relevant to human sepsis. Such models include intravascular infusion of endotoxin or live bacteria, bacterial peritonitis, cecal ligation and perforation, soft tissue infection, pneumonia or meningitis models using different animal species including rats, mice, rabbits, dogs, pigs, sheep, and nonhuman primates. Despite several limitations, animal models remain essential in the development of all new therapies for sepsis and septic shock because they provide fundamental information about the pharmacokinetics, toxicity, and mechanism of drug action that cannot be replaced by other methods. New therapeutic agents should be studied in infection models, even after the initiation of the septic process. Furthermore, debility conditions need to be reproduced to avoid the exclusive use of healthy animals, which often do not represent the human septic patient.

IntroductionPatients undergoing mechanical ventilation (MV) are frequently administered prolonged and/or high doses of opioids which when removed can cause a withdrawal syndrome and difficulty in weaning from MV. We tested the hypothesis that the introduction of enteral methadone during weaning from sedation and analgesia in critically ill adult patients on MV would decrease the weaning time from MV.MethodsA double-blind randomized controlled trial was conducted in the adult intensive care units (ICUs) of four general hospitals in Brazil. The 75 patients, who met the criteria for weaning from MV and had been using fentanyl for more than five consecutive days, were randomized to the methadone (MG) or control group (CG). Within the first 24 hours after study enrollment, both groups received 80% of the original dose of fentanyl, the MG received enteral methadone and the CG received an enteral placebo. After the first 24 hours, the MG received an intravenous (IV) saline solution (placebo), while the CG received IV fentanyl. For both groups, the IV solution was reduced by 20% every 24 hours. The groups were compared by evaluating the MV weaning time and the duration of MV, as well as the ICU stay and the hospital stay.ResultsOf the 75 patients randomized, seven were excluded and 68 were analyzed: 37 from the MG and 31 from the CG. There was a higher probability of early extubation in the MG, but the difference was not significant (hazard ratio: 1.52 (95% confidence interval (CI) 0.87 to 2.64; P = 0.11). The probability of successful weaning by the fifth day was significantly higher in the MG (hazard ratio: 2.64 (95% CI: 1.22 to 5.69; P < 0.02). Among the 54 patients who were successfully weaned (29 from the MG and 25 from the CG), the MV weaning time was significantly lower in the MG (hazard ratio: 2.06; 95% CI 1.17 to 3.63; P < 0.004).ConclusionsThe introduction of enteral methadone during weaning from sedation and analgesia in mechanically ventilated patients resulted in a decrease in the weaning time from MV.

Poli de Figueiredo LF, Biberthaler P, Simao Filho C, Hauser C, Mutschler W, Jochum M. Measurement of S-100B for risk classification of victims sustaining minor head injury -first pilot study in Brazil. Clinics. 2006;61(1):41-6.BACKGROUND: Release of the neuronal protein S-100B into the circulation has been suggested as a specific indication of neuronal damage. The hypothesis that S-100B is a useful and cost-effective screening tool for the management of minor head injuries was tested. METHODS: Fifty consecutive patients sustaining isolated minor head injury were prospectively evaluated in the emergency room of a Brazilian hospital by routine cranial computed tomography scan. Venous blood samples (processed to serum) were assssayed for S-100B using a newly developed immunoassay test kit. Twenty-one normal healthy individuals served as negative controls. Data are presented as median and 25 to 75 percentiles. RESULTS: Patients reached the emergency room an average of 45 minutes (range: 30-62 minutes) after minor head injury. Six of 50 patients (12%) showed relevant posttraumatic lesions in the initial cranial computed tomography scan and were counted as positive. The median systemic concentration of S-100B in those patients was 0.75 µg/L (range: 0.66-6.5 µg/L), which was significantly different (U-test, P < .05) from the median concentration of 0.26 µg/L (range: 0.12-0.65 µg/L), of patients without posttraumatic lesions as counted by the cranial computed tomography. A sensitivity of 100%, a specificity of 20%, a positive predictive value of 15%, and a negative predictive value of 100% was calculated for the detection of patients suffering from intracranial lesions. CONCLUSIONS: Protein S-100B had a very high sensitivity and negative predictive value and could have an important role in ruling out the need for cranial computed tomography scan after minor head injury. This appears to be of substantial clinical relevance, particularly in countries where trauma incidence is high and medical resources are limited, such as in Brazil.

Westphal GA, Silva E, Gonçalves AR Caldeira Filho M, Poli-de-Figueiredo LF. Pulse oximetry wave variation as a noninvasive tool to assess volume status in cardiac surgery. Clinics. 2009;64(4):337-43. OBJECTIVE:To compare variations of plethysmographic wave amplitude (∆Ppleth) and to determine the percent difference between inspiratory and expiratory pulse pressure (∆Pp) cutoff values for volume responsiveness in a homogenous population of postoperative cardiac surgery patients. INTRODUCTION: Intra-thoracic pressure variations interfere with stroke volume variation. Pulse pressure variations through arterial lines during mechanical ventilation have been recommended for the estimation of fluid responsiveness. Pulse oximetry may offer a non-invasive plethysmographic method to evaluate pulse pressure; this may be useful for guiding fluid replacement. METHODS: Controlled, prospective study in cardiac surgery patients under controlled ventilation. Simultaneous digital recordings of arterial pressure and plethysmographic waves were performed. ∆Pp, systolic pressure (∆Ps), ∆Ppleth, and systolic component (∆Spleth) were calculated. A ∆Pp ≥ 13% identified fluid-responsive patients. Volume expansion was performed in responsive subjects. Systolic and amplitude components of pressure and plethysmographic waves were compared. RESULTS: In 50 measurements from 43 patients, ∆Pp was correlated with (Ppleth (r=0.90, p<0.001), (Ps (r=0.90, p<0.001), and (Spleth (r=0.73, p<0.001). An aArea under ROC curve (AUC) identified the fluid responsiveness thresholds: (Ppleth of 11% (AUC = 0.95±0.04), (Ps of 8% (AUC=0.93±0.05), and (Spleth of 32% (AUC=0.82±0.07). A (Ppleth value ≥ 11% predicted (Pp ≥ 13% with 100% specificity and 91% sensitivity. Volume expansion, performed in 20 patients, changed (Pp, (Ppleth, (Ps and (Spleth significantly (p<0.008). CONCLUSIONS: ∆Ppleth is well correlated with ∆Pp and constitutes a simple and non-invasive method for assessing fluid responsiveness in patients following cardiac surgery.

Pulse pressure (DeltaPp) and systolic pressure (DeltaPs) variations have been recommended as predictors of fluid responsiveness in critically ill patients. We hypothesized that changes in DeltaPp and DeltaPs parallel alterations in stroke volume (SV) and cardiac output (CO) during hemorrhage, shock, and resuscitation. In anesthetized and mechanically ventilated mongrel dogs, a graded hemorrhage (20 mL/min) was induced to a target mean arterial pressure (MAP) of 40 mm Hg, which was maintained for additional 30 min. Total shed-blood volume was then retransfused at a 40 mL/min rate. CO, SV, right atrial pressure (RAP), pulmonary artery occlusion pressure (PAOP), and continuous mixed venous oxygen saturation (SvO(2)) were assessed. Both DeltaPp and DeltaPs were calculated from direct arterial pressure waveform. Removal of about 9% of estimated blood volume promoted a reduction in SV (14.8 +/- 2.2 to 10.6 +/- 1.3 mL, P < 0.05). At approximately 18% blood volume removal, significant changes in CO (2.4 +/- 0.2 to 1.5 +/- 0.2 mL/min, P < 0.05), DeltaPp (12.6 +/- 1.4 to 15.8 +/- 2.0%, P < 0.05), and SvO(2) (82 +/- 1.4 to 73 +/- 1.7%, P < 0.05) were observed. Alterations in MAP, RAP, PAOP, and DeltaPs could be detected only after each animal had lost over 36% of estimated initial blood volume. There was correlation between blood volume loss and SV, CO, and SvO(2), as well as between blood loss and MAP, DeltaPp, and DeltaPs. Blood volume loss showed no correlation with cardiac filling pressures. DeltaPp is a useful, early marker of SV and CO for the assessment of cardiac preload changes in hemorrhagic shock, while cardiac filling pressures are not.

We tested the hypothesis that the dynamic evaluation of central venous pressure (CVP) amplitude could be a reliable predictor of fluid responsiveness in patients under mechanical ventilation, similar to the variation of arterial pulse pressure (DeltaPp). Thirty postcardiac surgery patients, under mechanical ventilation, were evaluated. The percentual difference between inspiratory (Ppins) and expiratory pulse pressure (Ppins) was so calculated: DeltaPp (%) = 100 x (Ppins - Ppexp)/[(Ppins + Ppexp)/2]. The respiratory variation of CVP curves amplitude were calculated by determining the percentual difference between inspiratory (CVPpins) and expiratory (CVPpexp) variation using vena cava "pressure" collapsibility index according the following formula: Cvci (%) = [(CVPpexp - CVPpins)/CVPpexp] x 100. There was a correlation between DeltaPp and Cvci (Pearson correlation coefficient, r = 0.45). Receiver operating characteristic curves showed that the Cvci value more than or equal to 5% predicted DeltaPp more than or equal to 13% with 91% specificity, 89% sensitivity, and AUC of 0.90. Therefore, Cvci presented a good agreement with DeltaPp (kappa = 0.76) to identify potential fluid responders (patients with DeltaPp > or =13%). In 9 potential fluid responders, both DeltaPp and Cvci significantly decreased from 18% +/- 8% to 8% +/- 6% (P < 0.004) and 23% +/- 15% to 7% +/- 6% (P < 0.004), respectively, after fluid replacement. Our findings suggest that vena cava "pressure" collapsibility index can be used as a marker of fluid responsiveness in postcardiac surgery patients under mechanical ventilation, such as arterial pulse pressure respiratory variation.

Nakagawa NK; Jukemura J, Aikawa P, Nogueira RA, Poli-de-Figueiredo LF, and Sannomiya P. In vivo observation of mesenteric leukocyte-endothelial interactions after cecal ligation/puncture and surgical sepsis source control. Clinics. 2007;62(3):321-6. PURPOSE: Cecal ligation and puncture (CLP) has been used as a useful model for the induction of polymicrobial sepsis. Necrotic tissue resection and peritoneal lavage (REL) are the surgical procedures for controlling perforated appendicitis. The aim of this study was to evaluate leukocyte-endothelial interactions in the rat mesentery in vivo after CLP and REL. METHODS: Thirty-seven male Wistar rats (250-300 g) underwent laparotomy and were randomly assigned to the following groups: 1) SHAM; 2) CLP: animals submitted to CLP, 3) CLP+REL: animals submitted to CLP and REL. Mesenteric leukocyteendothelial interactions were studied by intravital microscopy assessed once in each animal (3-5 postcapillary venules, 15-25 µm diameter) 24 hours after intervention. Follow-up was performed in all animals; this included analysis of glycemia, lactate, hematocrit, white blood cell count as well as a functional score that was the sum of scoring on the following parameters: alertness, mobility, piloerection, diarrhea, encrusted eyes, and dirty nose and tail. RESULTS: None of the animals showed significant changes in body weight (265 ± 20 g) or in hematocrit levels (46% ± 2%) during the experimental protocol. Compared to SHAM animals, CLP animals showed an increased number of rolling (2x), adherent, and migrating leukocytes (7x) in the mesenteric microcirculation, an increase in blood glucose (136 ± 8 mg/dL), lactate (3.58 ± 0.94 mmol/L), white cell count (23,570 ± 4,991 cells/mm 3 ) and functional alterations (score 11 ± 1), characterized by impaired alertness and mobility, and presence of piloerection, diarrhea, encrusted eyes, and dirty nose and tail. The REL procedure normalized the number of rolling, adherent, and migrated leukocytes in the mesentery; glycemia; lactate; and white blood cell count. The REL procedure also improved the functional score (7 ± 1). CONCLUSION: Local and systemic inflammation was induced by CLP, while REL completely overcame the inflammatory process.

In the event of severe head trauma and hemorrhagic shock, the use of HSS 3% and larger volumes of LR promote similar systemic and cerebral hemodynamic benefits. However, a lower ICP was observed after HSS 3% than after LR.