Nitrosative and oxidative stresses contribute to post-ischemic liver injury following severe hemorrhagic shock: the role of hypoxemic resuscitation.

PURPOSE: Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury. METHODS: Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO(2) = 95-105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO(2) = 35-40 mmHg) followed, modifying the FiO(2). Animals not subjected to shock constituted the sham group (n = 11, PaO(2) = 95-105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed. RESULTS: Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor--alpha, interleukin (IL) -1ß and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals. CONCLUSIONS: Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory response and oxidative and nitrosative stresses.

Fasciitis and septic shock complicating retrocecal appendicitis.

INTRODUCTION: A case of fasciitis and septic shock complicating retrocecal appendicitis is presented. CASE REPORT: A 52-year-old man presented to the Emergency Department with lumbar pain, fever of recent onset and subsequently developed septic shock attributed to fasciitis of abdominal, flank and groin region. On intensive care unit, he was managed with broad-spectrum intravenous antibiotics and surgical debridement. An abdominal computed tomography scan confirmed the findings of fasciitis and was negative for intra-abdominal pathology. In the following days, an enterocutaneous fistula with foul smelling fluid was noted. A new surgical exploration revealed the presence of a ruptured retrocecal appendix, and right hemicolectomy was performed. The postoperative period was long but uneventful. CONCLUSION: Retrocecal appendicitis can rarely be presented as deteriorating cellulitis-fasciitis in the right abdominal, flank or groin region, with or without abdominal symptoms.

Cardiac arrest provoked by itraconazole and amiodarone interaction: a case report.

INTRODUCTION: Azoles, and specifically itraconazole, are often prescribed for the treatment of fungal diseases or empirically for persistent sepsis in patients who are neutropenic or in intensive care. Occasional cardiovascular adverse events have been associated with itraconazole use, and are usually attributed to the interaction of itraconazole with cisapride, terfenadine or digoxin. Its interaction with amiodarone has not been previously described. CASE PRESENTATION: A 65-year-old Caucasian man was admitted to the Intensive Care Unit at our facility for an extensive ischemic stroke associated with atrial fibrillation. Due to rapid ventricular response he was started on intravenous amiodarone and few days later itraconazole was also prescribed for presumed candidemia. After receiving the first dose our patient became profoundly hypotensive but responded rapidly to fluids and adrenaline. Then, two months later, itraconazole was again prescribed for confirmed fungemia. After receiving the first dose via a central venous catheter our patient became hypotensive and subsequently arrested. He was resuscitated successfully, and as no other cause was identified the arrest was attributed to septic shock and his antifungal treatment was changed to caspofungin. When sensitivity test results became available, antifungal treatment was down-staged to itraconazole and immediately after drug administration our patient suffered another arrest and was once again resuscitated successfully. This time the arrest was related to itraconazole, which was discontinued, and from then on our patient remained stable until his discharge to our neurology ward. CONCLUSIONS: Itraconazole and amiodarone coadministration can lead to serious cardiovascular adverse events in patients who are critically ill. Intensivists, pharmacists and medical physicians should be aware of the interaction of these two commonly used drugs.

Hypoxemic resuscitation from hemorrhagic shock prevents lung injury and attenuates oxidative response and IL-8 overexpression.

We investigated whether hypoxemic resuscitation from hemorrhagic shock prevents lung injury and explored the mechanisms involved. We subjected rabbits to hemorrhagic shock for 60 min by exsanguination to a mean arterial pressure of 40 mm Hg. By modifying the fraction of the inspired oxygen, we performed resuscitation under normoxemia (group NormoxRes, P(a)O(2)=95-105 mm Hg) or hypoxemia (group HypoxRes, P(a)O(2)=35-40 mm Hg). Animals not subjected to shock constituted the sham group (P(a)O(2)=95-105 mm Hg). We performed bronchoalveolar lavage (BAL) fluid, lung wet-to-dry weight ratio, and morphological studies. U937 monocyte-like cells were incubated with BAL fluid from each group. Cell peroxides, malondialdehyde, proteins, and cytokines in the BAL fluid were lower in sham than in shocked animals and in HypoxRes than in NormoxRes animals. The inverse was true for ascorbic acid and reduced glutathione. Lung edema, lung neutrophil infiltration, myeloperoxidase, and interleukin (IL)-8 gene expression were reduced in lungs of HypoxRes compared with NormoxRes animals. A colocalized higher expression of IL-8 and nitrotyrosine was found in lungs of NormoxRes animals compared to HypoxRes animals. The BAL fluid of NormoxRes animals compared with HypoxRes animals exerted a greater stimulation of U937 monocyte-like cells for proinflammatory cytokine release, particularly for IL-8. In the presence of p38-MAPK and Syk inhibitors and monosodium urate crystals, IL-8 release was reduced. We conclude that hypoxemic resuscitation from hemorrhagic shock ameliorates lung injury and reduces oxygen radical generation and lung IL-8 expression.

Oral atovaquone for the treatment of severe Pneumocystis jirovecii pneumonia in a patient with glucose-6-phosphate dehydrogenase deficiency.

We present a case of severe Pneumocystis jirovecii pneumonia and coexisting cytomegalovirus infection in a glucose-6-phosphate dehydrogenase (G6PD) enzyme deficient woman with anaplastic astrocytoma on temozolomide and corticosteroid therapy. She was successfully treated with oral atovaquone and ganciclovir. Atovaquone represents a safe alternative in severe Pneumocystis infection when trimethoprim-sulfamethoxazole (co-trimoxazole) is contraindicated.

Reasons of PEG failure to eliminate gastroesophageal reflux in mechanically ventilated patients.

AIM: To investigate factors predicting failure of percutaneous endoscopic gastrostomy (PEG) to eliminate gastroesophageal reflux (GER). METHODS: Twenty-nine consecutive mechanically ventilated patients were investigated. Patients were evaluated for GER by pH-metry pre-PEG and on the 7th post-PEG day. Endoscopic and histologic evidence of reflux esophagitis was also carried out. A beneficial response to PEG was considered when pH-metry on the 7th post-PEG day showed that GER was below 4%. RESULTS: Seventeen patients responded (RESP group) and 12 did not respond (N-RESP) to PEG. The mean age, sex, weight and APACHE II score were similar in both groups. GER (%) values were similar in both groups at baseline, but were significantly reduced in the RESP group compared with the N-RESP group on the 7th post-PEG day [2.5 (0.6-3.8) vs 8.1 (7.4-9.2, P < 0.001)]. Reflux esophagitis and the gastroesophageal flap valve (GEFV) grading differed significantly between the two groups (P = 0.031 and P = 0.020, respectively). Histology revealed no significant differences between the two groups. CONCLUSION: Endoscopic grading of GEFV and the presence of severe reflux esophagitis are predisposing factors for failure of PEG to reduce GER in mechanically ventilated patients.

Outcome in 1,000 head injury hospital admissions: the Athens head trauma registry.

BACKGROUND: The aim of this study was to establish a head trauma registry to (a) examine demographics, etiology, severity, clinical course, and outcome; (b) compare results with previous published series; (c) identify causes of bad outcomes; and (d) propose methods to improve therapy and prognosis. METHODS: The following data were collected on 1,000 consecutive victims with head injury over 14 years of age admitted during a 4-year period: demographic characteristics, cause of injury, clinical variables, neuroimaging, therapy data, and outcome in 6 months. RESULTS: Seventy-four percent were men, and mean age was 43 years. Seventy-one percent suffered injuries due to road crashes, 14% due to alcohol, and 2% due to substances. The secondary transfer rate was 49%. For severe injuries, the time intervals from incident to hospital and subsequently to neurosurgical unit were 35 minutes and 4 hours, respectively. In 65% and 72% of cases, there was no record of preresuscitation hypoxia or hypotension, respectively, whereas suspected or definite episodes of hypoxia and hypotension were 27% and 13%, respectively. Most cases were mild trauma (63%), the remaining were severe (26%) and moderate (11%) injuries. Severe systemic trauma coexisted in 18%. Cranial surgery rate was 19% and it increased to 39% in severe trauma. The 6-month overall good outcome was 71%, with lower rates in moderate (58%) and severe (24%) injuries. CONCLUSIONS: The organization of Greece's first head injury registry offered an important preliminary core data concerning brain trauma etiology, management, and long-term outcome.

The level of hypotension during hemorrhagic shock is a major determinant of the post-resuscitation systemic inflammatory response: an experimental study.

BACKGROUND: To evaluate whether the level of hypotension during hemorrhagic shock may influence the oxidative and inflammatory responses developed during post-ischemic resuscitation. METHODS: Fifteen rabbits were equally allocated into three groups: sham-operated (group sham); bled within 30 minutes to mean arterial pressure (MAP) of 40 mmHg (group shock-40); bled within 30 minutes to MAP of 30 mmHg (group shock-30). Shock was maintained for 60 min. Resuscitation was performed by reinfusing shed blood with two volumes of Ringer's lactate and blood was sampled for estimation of serum levels aminotransferases, creatinine, TNF-alpha, IL-1beta, IL-6, malondialdehyde (MDA) and total antioxidant status (TAS) and for the determination of oxidative burst of polymorhonuclears (PMNs) and mononuclear cells (MCs). RESULTS: Serum AST of group shock-30 was higher than that of group shock-40 at 60 and 120 minutes after start of resuscitation; serum creatinine of group shock-30 was higher than group shock-40 at 120 minutes. Measured cytokines, MDA and cellular oxidative burst of groups, shock-40 and shock-30 were higher than group sham within the first 60 minutes after start of resuscitation. Serum concentrations of IL-1beta, IL-6 and TNF-alpha of group shock-30 were higher than group shock-40 at 120 minutes (p < 0.05). No differences were found between two groups regarding serum MDA and TAS and oxidative burst on PMNs and MCs but both groups were different to group sham. CONCLUSION: The level of hypotension is a major determinant of the severity of hepatic and renal dysfunction and of the inflammatory response arising during post-ischemic hemorrhagic shock resuscitation. These findings deserve further evaluation in the clinical setting.

The effect of hypoxemic resuscitation from hemorrhagic shock on blood pressure restoration and on oxidative and inflammatory responses.

OBJECTIVE: We investigated whether hypoxemic resuscitation from hemorrhagic shock prevents the late circulatory instability and attenuates the oxidative and inflammatory responses associated with the standard strategy. DESIGN AND SETTING: Prospective, randomized, controlled animal study in an experimental laboratory of a university intensive care unit. SUBJECTS: Thirty-one New Zealand white rabbits weighting 3.1-3.4 kg INTERVENTIONS: Anesthetized animals were subjected to hemorrhagic shock by exsanguinations to a mean arterial pressure of 40 mmHg for 60 min. Resuscitation was performed by reinfusing the shed blood for 30 min under normoxemia (PaO(2) 95-105 mmHg, control group, n=10) or hypoxemia (PaO(2) 35-40 mmHg, hypox-res group, n=10); Ringer's lactate was given from 30 to 60 min to restore arterial pressure within baseline values. A sham group was assigned (n=11). Animals were recorded for 120 min postresuscitation and for further 360 min to assess the early mortality rate. MEASUREMENTS AND RESULTS: Hypoxemic resuscitation compared with normoxemic resuscitation from hemorrhagic shock was associated with (a) a better hemodynamic condition assessed by the gradual restoration of blood pressure, higher urinary output associated with less fluid infusion; (b) lower reactive oxygen species production assessed by the reduced blood geometric mean fluorescence intensity, lower malondialdehyde, and higher ratio of reduced to total glutathione levels; (c) attenuation in the plasma concentrations of IL-1beta, TNF-alpha, and IL-6; and (d) no difference in mortality rate. CONCLUSIONS: Hypoxemic resuscitation from hemorrhagic shock is more efficient than normoxemic in restoring the blood pressure and in attenuating the excessive oxidative and inflammatory responses observed during normoxemic resuscitation.

Head injury mortality in a geriatric population: differentiating an "edge" age group with better potential for benefit than older poor-prognosis patients.

A comparison of outcomes between different modes of head-injury treatment in the elderly has important bearing on questions of cost-effectiveness and medical ethics. Here, we have examined rates of mortality in elderly head-trauma victims to determine whether it is valid to differentiate an "edge" age group of younger elderly patients, 65-74 years of age, from older elderly patients, considering possible benefit from intensive treatment and surgical intervention. We collected data from 1926 cases of head trauma and separated them into three age groups: 14-64 years, 65-74 years, and 75 years or older. We then compared these groups with respect to cause of injury, severity of injury, and whether or not treatment included either admission to an Intensive Care Unit (ICU) or surgical intervention. We found that road traffic accidents were the major cause of head injury in the younger age group, whereas in the elderly falls predominated. Mortality was higher in the elderly in all the head injury severity subgroups. Young subjects with a Glasgow Coma Scale (GCS) score of less than or equal to 8 tended to benefit from ICU treatment whereas patients 75 and over did not, regardless of their severity of injury. For these patients who were in the 65-74 age group, the data suggested that some benefit was likely. Patients 75 and older were significantly less likely to survive surgical intervention than younger patients. We conclude that it is valid to treat patients in the age group 65-74 years as a separate group from those patients 75 and older. Patients in this younger subset of the elderly may benefit from ICU treatment or surgical intervention. However, the patients in our older subset of elderly patients clearly did not, and they had a significantly higher risk of surgical mortality.

Monocytes as a site of production of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) in the septic host.

The role of blood monocytes in the secretion of soluble triggering receptor expressed on myeloiod cells (sTREM-1) was studied in 90 patients with septic syndrome due to ventilator-associated pneumonia. Blood monocytes were isolated on 7 consecutive d after initiation of symptoms. Monocytes were incubated in the absence or presence of LPS and concentrations of sTREM-1 and TNFalpha in cell supernatants and serum were estimated by an enzyme-immunoassay. sTREM-1 and TNFalpha were consistently present at detectable levels in the cell supernatants. LPS induced increased levels of TNFalpha but not of sTREM-1. Supernatants recovered from monocytes on d 1 showed levels of sTREM-1 higher than those recovered on any of the following 6 d (p<0.05); these levels were higher in non-survivors than in survivors. Supernatants recovered from monocytes on d 1 of patients with severe sepsis had elevated concentrations of sTREM-1 compared to patients with septic shock and similar to patients with sepsis. A negative correlation was found between levels of sTREM-1 in the cell supernatants and the percentage of apoptotic monocytes. In essence, the above results suggest that monocytes contribute to the production of sTREM-1 in the event of septic syndrome.

Aspergillus endocarditis in a native valve after amphotericin B treatment.

Systemic infection with Aspergillus fumigatus is an opportunistic disease that affects mainly immunocompromised hosts and is associated with a high mortality rate. We report a case of A. fumigatus endocarditis after an episode of thrombotic thrombocytopenic purpura. Diagnosis was established after sudden rupture of posterior papillary muscle of the normal native mitral valve. Soon after mitral valve replacement, Aspergillus endocarditis recurred, associated with multiple peripheral emboli, which necessitated a second operation.