COVID-19 rebound after oral treatment in a nursing home facility: A case series.

Paxlovid (nirmatrevir/ritonavir) is a 2 drug regimen taken together twice daily for 5 days was authorized for emergency use for nonhospitalized patients who are at risk for the progression of coronavirus disease (COVID-19). However, recurrence of symptoms 2-8 days after completing the treatment course has been recently recognized. In some cases patients tested negative on a direct SARS-CoV-2 viral test and then tested positive again (rebound COVID-19). The disease is mild and requires no additional antiviral treatment. Data are limited based on anecdotal case reports and few studies. According to the available data it is unclear if rebound symptoms are due to the drug treatment, drug resistance, re-infection or impaired immunity.

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.

Comparison of the sequential organ failure assessment score with the King's College Hospital criteria and the model for end-stage liver disease score for the prognosis of acetaminophen-induced acute liver failure.

Acetaminophen-induced acute liver failure (ALF) is a complex multiorgan illness. An assessment of the prognosis is essential for the accurate identification of patients for whom survival without liver transplantation (LT) is unlikely. The aims of this study were the comparison of prognostic models [King's College Hospital (KCH), Model for End-Stage Liver Disease, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II)] and the identification of independent prognostic indicators of outcome. We evaluated consecutive patients with severe acetaminophen-induced ALF who were admitted to the intensive care unit. At admission, demographic, clinical, and laboratory parameters were recorded. The discriminative ability of each prognostic score at the baseline was evaluated with the area under the receiver operating characteristic curve (AUC). In addition, using a multiple logistic regression, we assessed independent factors associated with outcome. In all, 125 consecutive patients with acetaminophen-induced ALF were evaluated: 67 patients (54%) survived with conservative medical management (group 1), and 58 patients (46%) either died without LT (28%) or underwent LT (18%; group 2). Group 1 patients had significantly lower median APACHE II (10 versus 14) and SOFA scores (9 versus 12) than group 2 patients (P < 0.001). The independent indicators associated with death or LT were a longer prothrombin time (P = 0.007), the inspiratory oxygen concentration (P = 0.005), and the lactate level at 12 hours (P < 0.001). The KCH criteria had the highest specificity (83%) but the lowest sensitivity (47%), and the SOFA score had the best discriminative ability (AUC = 0.79). In conclusion, for patients with acetaminophen-induced ALF, the SOFA score performed better than the other prognostic scores, and this reflected the presence of multiorgan dysfunction. A further evaluation of SOFA with the KCH criteria is warranted.

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.

Administration of human protein C improves survival in an experimental model of sepsis.

OBJECTIVE: Study the effect of human protein C (PC) concentrate administration on organ damage and survival in septic rats. DESIGN: Animal study. SETTING: University laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Cecal ligation and puncture (CLP) was performed in 210 rats. Rats were randomly assigned to receive either human protein C (PC) IV 1, 7, and 13 hrs after CLP (CLP+PC) or placebo (CLP). Septic animals were again randomized in a survival group (CLP: n = 50 and CLP+PC: n = 40) that was monitored for 60 hrs and time groups (CLP: n = 60 and CLP+PC: n = 60) that were killed at 6, 12, 24, 36, 48, and 60 hrs after CLP. Brain, heart, lung, liver, kidney, gastric, and colon tissue were removed and postfixed in paraffin sections. MEASUREMENTS AND MAIN RESULTS: PC infusion increased PC serum levels in early sepsis (median 7.25) compared with late sepsis (median 2, p = .001). Activated protein C/a1-antitrypsin complex levels in the CLP+PC group were significantly increased in late sepsis (60 hrs after CLP) compared with early sepsis (6, 12, and 24 hrs after CLP, p = .009, p = .004, and p = .008, respectively) and to late septic CLP and normal rats (p = .005 and p = .007, respectively). Their IL-6 and tumor necrosis factor a plasma levels were decreased (by 27% and 25%, respectively) at 6 hrs compared with placebo (p = .008 and p = .016). Their serum PC levels were also decreased in CLP+PC survivors compared with nonsurvivors of the same group (median = 1.5 vs. median = 7, p = .001). Apoptosis was reduced in brain (10% vs. 77.8%, p < .001), stomach (66.7% vs. 100%, p < .002) and intestine (33.3% vs. 85.2%, p < .001) compared with placebo. Finally, the survival of septic rats treated with human PC was significantly increased compared with placebo (75% vs. 54%, p = .033). CONCLUSIONS: Human Protein C administration increased survival in septic rats, decreased plasma inflammatory cytokines levels and tissue injury in vital organs.

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.

Ampicillin-sulbactam: an update on the use of parenteral and oral forms in bacterial infections.

Ampicillin-sulbactam has a wide range of antibacterial activity that includes Gram-positive and Gram-negative aerobic and anaerobic bacteria. However, the drug is not active against Pseudomonas aeruginosa and pathogens producing extended-spectrum beta-lactamases. The combination could be considered particularly active against Acinetobacter baumannii infections due to the intrinsic activity of sulbactam. The drug is indicated as empirical therapy for a broad range of community acquired infections supervened in adults or children and is effective in either parenteral (ampicillin-sulbactam) or oral (as a mutual prodrug sultamicillin) form. In clinical trials, sultamicillin has proved clinically and bacteriologically effective in adults and children against a variety of frequently encountered infections, including mild upper and lower respiratory tract infections, urinary tract infections, diabetic foot and skin and soft tissue infections. Furthermore, adverse effects rarely occur with the diarrhoea to represent the most commonly reported. The parenteral ampicillin-sulbactam is indicated for community infections of mild-to-moderate severity acquired infections such as intra-abdominal or gynecological. Moreover, it seems to represent the alternative of choice for the treatment of A. baumannii infections for carbapenem-resistant strains in the nosocomial setting. Thus, ampicillin-sulbactam remains a valuable agent in the physician's armamentarium in the management of adult and pediatric infections.

Hypoxemic resuscitation after hemorrhagic shock is accompanied by reduced serum levels of angiopoietin-2.

BACKGROUND: To investigate whether angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) are implicated in the hypoxemic resuscitation from hemorrhagic shock. METHODS: Twenty rabbits were subjected to hemorrhagic shock after blood exsanguination; resuscitation was performed by infusion of the shed blood in ten rabbits under normoxemic conditions (NormoxRes) and in 10 under hypoxemic conditions (HypoxRes); four rabbits were subjected to sham operation. Serum was drawn at serial time intervals; serum was applied for stimulation of U937 monocytes. RESULTS: Serum concentrations of Ang2 were higher in the NormoxRes group compared to the HypoxRes group at 90 min (p: 0.049) and at 120 min (p: 0.028). Serum concentrations of VEGF did not differ between groups. Concentrations of VEGF in the supernatants of U937 stimulated with sera of all groups were below detection limit. The wet to dry lung ratio of the HypoxRes group was significantly lower than the NormoxRes group (p<0.0001). CONCLUSIONS: Hypoxemic resuscitation from hemorrhagic shock is a process accompanied by reduced serum levels of Ang2. These findings add significantly to our understanding of that experimental treatment strategy of resuscitation.

Administration of Human Protein-C concentrate prevents apoptotic brain cell death after experimental sepsis.

Activated Protein C renders anti-apoptotic properties in neurons and endothelial cells. The aim of the present study was to evaluate the in vivo cytoprotective role of Protein C zymogen (PC) administration in septic rat brain. Male Wistar rats (n=60) were subjected to sepsis via Cecal Ligation and Puncture (CLP). Animals were randomly divided either to receive 100 IU/kg human PC concentrate at 1, 7 and 13 h post CLP (CLP+PC group) or placebo treatment (CLP group). At pre-specified time points (6, 12, 24, 36, 48 and 60 h post CLP) five animals from either group were euthanized and the brain tissue was removed. Apoptosis in both neurons (Neu-N+) and astroglia (GFAP+) was assessed by flow cytometry using 7-aminoactinomycin D (7AAD). Immunohistochemical detection of cleaved caspase 3, bax, bcl-2, cytochrome c and caspase 8 was also performed. PC treated animals had significantly reduced apoptosis in neurons at 6 and 24 h post CLP (p=0.04 and p=0.016 respectively) and necrosis at 6, 12 and 60 h post CLP (p=0.008, p=0.012 and p=0.032 respectively). Astrocyte necrosis was also decreased in septic rats receiving PC (6, 12 and 60 h post CLP p=0.008, p=0.016 and p=0.008 respectively). In addition, active caspase 3, bax, cytochrome c and caspase 8 expression was significantly decreased during early sepsis (6-36 h) while bcl-2 expression was increased (24 h p=0.001 and 60 h p=0.001) in the PC treated animals compared to placebo. PC concentrate administration in experimental sepsis produced a time dependent inhibition of apoptosis in rat neurons and astrocytes. The inhibition of sepsis related apoptosis concerned both the mitochondrial and caspase 8 dependent pathways.

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.

Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia.

OBJECTIVE: To compare the safety and efficacy of ampicillin/sulbactam (Amp/Sulb) and colistin (COL) in the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP). METHODS: A prospective cohort study in adult critically ill patients with VAP. Patients were randomly assigned to receive Amp/Sulb (9 g every 8h) or COL (3 MIU every 8h) intravenously. Dosage was adjusted according to creatinine clearance. RESULTS: A total of 28 patients were enrolled (15 COL, 13 Amp/Sulb). Resolution of symptoms and signs occurred in 60% (9/15) of the COL group and 61.5% (9/13) of the Amp/Sulb group, improvement in 13.3% (2/15) vs. 15.3% (1/13) and failure in 26.6% (4/15) vs. 23% (3/13), respectively. The difference was not statistically significant. Bacteriologic success was achieved in 66.6% (10/15) vs. 61.5% (8/13) in the COL and Amp/Sulb groups, respectively (p<0.2). Mortality rates (14 days and 28 days) were 15.3% and 30% for the Amp/Sulb and 20% and 33% for the COL group, respectively. Adverse events were 39.6% (including 33% nephrotoxicity) for the COL group and 30.7% (15.3% nephrotoxicity) for the Amp/Sulb group (p=NS). CONCLUSION: Colistin and high-dose ampicillin/sulbactam were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP.

Prognostic models in cirrhotics admitted to intensive care units better predict outcome when assessed at 48 h after admission.

BACKGROUND AND AIM: The accuracy of prognostic models in critically ill cirrhotics at admission to intensive care units (ICU) may be unreliable. Predictive accuracy could be improved by evaluating changes over time, but this has not been published. The aim of the present study was to assess the performance of prognostic models in cirrhotics at admission (baseline) and at 48 h to predict mortality in the ICU or within 6 weeks after discharge from the ICU. METHODS: One hundred and twenty-eight cirrhotics (77 males, mean age 49 +/- 11.3 years) were consecutively admitted and alive 48 h after admission with 89% on mechanical ventilation, 76% on inotrope support, and 42% with renal failure. Prognostic models used were Child-Turcotte-Pugh (CTP), Model for End-stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA), failing organ systems (FOS) at baseline and at 48 h, Deltascore (difference between baseline and at 48 h) and the mean score (MN - score admission + 48 h/2) which were compared by area under the receiver operating characteristic curves (AUC). RESULTS: Mortality was 54.7% (n = 70) due to multiple organ failure in 55%. CTP, MELD, APACHE II, SOFA and FOS performed better at 48 h (AUC: 0.78, 0.86, 0.78, 0.88 and 0.85, respectively) than at baseline (AUC: 0.75, 0.78, 0.75, 0.81 and 0.79, respectively). The mean score had better discrimination than the baseline score; the Deltascore had poor predictive ability (AUC < 0.70). SOFA score (48 h: 0.88, mean: 0.88) and FOS (mean: 0.88) had the best accuracy, with a SOFA and MN-SOFA > or = 10 predicting mortality in 93% and 91%, respectively, and MN-FOS > or = 1.5 in 98%. CONCLUSIONS: In cirrhotics, prognostic scores in the ICU at 48 h had better discrimination than baseline scores for short-term mortality. SOFA and FOS models had the best performance.

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.