Haemorrhagic shock secondary to a diffuse ulcerative enteritis after Ipilimumab and Nivolumab treatment for metastatic melanoma: a case report.

We provide a unique case of haemorrhagic shock complicating a corticosteroid-resistant diffuse ulcerative enteritis in a patient treated with a combination of an anti cytotoxic T-lymphocyte antigen-4 (CTLA4) and an anti programmed cell death protein 1 (PD-1) for metastatic melanoma. Immunotherapy has changed the perspective for the management of patients with metastatic melanoma but are also responsible for digestive complications mainly represented by immunomediated colitis. Digestive bleeding is common in patients with extensive colonic lesions but has never been described in enteritis independent of colitis. The patient with acute intestinal obstruction related ileitis without evidence of stricture on imaging and then had a gastro-intestinal bleed. In the absence of haemorrhagic lesions on upper gastrointestinal endoscopy, colonoscopy and computed tomography (CT) angiography, a surgical exploration with enteroscopy was performed. This revealed an extensive ulcerated jejunoileitis, with active bleeding, within a Meckel's diverticulum. Management included resection of the Meckel diverticulum with a transient double barrel ileostomy. Two infliximab infusions were given due to persistent bleeding. We observed a dramatic improvement after infliximab treatment with complete cessation of bleeding and no further need for transfusions. A complete mucosal healing has been achieved on enteroscopy at 3 months with disappearance of histological inflammatory lesions. This observation suggests that infliximab represents a therapeutic option in severe enteritis and may be as effective as in more moderate immune-mediated enterocolitis.

The Influence of Hemorrhagic Shock on the Disposition and Effects of Intravenous Anesthetics: A Narrative Review.

The need to reduce the dose of intravenous anesthetic in the setting of hemorrhagic shock is a well-established clinical dogma. Considered collectively,; the body of information concerning the behavior of intravenous anesthetics during hemorrhagic shock, drawn from animal and human data, confirms that clinical dogma and informs the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The physiologic changes during hemorrhagic shock can alter pharmacokinetics and pharmacodynamics of intravenous anesthetics. Decreased size of the central compartment and central clearance caused by shock physiology lead to an altered dose-concentration relationship. For most agents and adjuncts, shock leads to substantially higher concentrations and increased effect. The notable exception is etomidate, which has relatively unchanged pharmacokinetics during shock. Increased concentrations lead to increased primary effect as well as increased side effects, notably cardiovascular effects. Pharmacokinetic changes are essentially reversed for all agents by fluid resuscitation. Propofol is unique among agents in that, in addition to the pharmacokinetic changes, it exhibits increased potency during shock. The pharmacodynamic changes of propofol persist despite fluid resuscitation. The persistence of these pharmacodynamic changes during shock is unlikely to be due to increased endogenous opiates, but is most likely due to increased fraction of unbound propofol. The stage of shock also appears to influence the pharmacologic changes. The changes are more rapid and pronounced as shock physiology progresses to the uncompensated stage. Although scant, human data corroborate the findings of animal studies. Both the animal and human data inform the rational selection and administration of intravenous anesthetics in the setting of hemorrhagic shock. The well-entrenched clinical dogma that etomidate is a preferred induction agent in patients experiencing hemorrhagic shock is firmly supported by the evidence. Propofol is a poor choice for induction or maintenance of anesthesia in severely bleeding patients, even with resuscitation; this can include emergent trauma cases or scheduled cases that routinely have mild or moderate blood loss.

[Devastating surgical complications after aflibercept chemotherapy]. / Devastadora complicación tras tratamiento con aflibercept.

BACKGROUND: The use of a new chemotherapy as adjuvant treatment of colorectal cancer is not free of complications. Monoclonal antibodies are associated with bleeding and intestinal perforations. OBJECTIVE: To report the case of a patient who developed a serious complication after treatment with an antiangiogenic drug for colorectal neoplasm. CLINICAL CASE: The case is presented of a 42-year-old male operated on due to subocclusive rectal cancer with metástasis at the time of diagnosis. Sixteen months after surgery during second-line adjuvant therapy, an intestinal perforation was observed with haemorrhage and intestinal leak to retroperitoneum and left lower extremity. Despite intensive medical and surgical treatment this complication had fatal consequences. CONCLUSIONS: Future research should be directed at obtaining biomarkers for the specific use of antiangiogenic agents in order to decrease the rate of adverse factors.

[Giant subcutaneous hematoma with hemorrhagic shock induced by goserelin acetate injection for prostate cancer : report of a case].

A 87-year-old man was diagnosed with prostate cancer (cT2aN0M0 Gleason score 4＋4 with initial prostate specific antigen of 23.4 ng/ml). Prostate cancer was treated with combined androgen blockade (goserelin acetate plus flutamide). He was administered goserelin acetate depot injection without any complications as an outpatient. However, 5 hours after he left the hospital, he came back to the hospital, complaining of lower abdominal pain. Abdominal computed tomography revealed a giant subcutaneous hematoma in the lower abdomen. Hemoglobin was 6.9 g/dl and blood pressure was lower than 80 mmHg. He was admitted and given a blood transfusion. Because of pre-disseminated intravascular coagulation score 6, it was hard to antagonize warfarin by Vitamin K (he had taken warfarin because of atrial fibrillation). Arteriography was performed and injury to a branch of the lower epigastric artery was found. Transcatheter arterial embolization was performed at the same time. Injecting goserelin acetate may cause severe arterial injury.

p-Hydroxyphenylpyruvate, an intermediate of the Phe/Tyr catabolism, improves mitochondrial oxidative metabolism under stressing conditions and prolongs survival in rats subjected to profound hemorrhagic shock.

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2-4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent.

Dabigatran anticoagulation and Stanford type A aortic dissection: lethal coincidence: Case report with literature review.

BACKGROUND: Novel oral anticoagulants are now encountered in patients needing emergency surgery. Knowledge and treatment options are limited. METHODS AND RESULT: We present the case of a 76-year-old patient who suffered from an acute Stanford type A aortic dissection, needing emergency surgical aortic repair. He was anticoagulated with dabigatran due to past atrial fibrillation. Despite haemodiafiltration, surgical revision and massive transfusion of packed red blood cells, fresh frozen plasma, platelets, coagulation factors, and recombinant factor VIIa, the patient died from intractable bleeding with sustained therapeutic levels of dabigatran. CONCLUSION: After reviewing the literature, we summarize the limited treatment options and show possible approaches for patients treated with dabigatran needing emergency surgery.

Effects of different resuscitation fluids on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection.

BACKGROUND: To investigate the effects of fluids resuscitation on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection. METHODS: Sixty Sprague-Dawley rats were randomly assigned to five groups, sham operation group (Group C) and four treated groups: no fluid resuscitation group (Group NF), groups resuscitated with Lactated Ringer's (LR),7.5% NaCl (HTS) and Hydroxyl ethyl starch (HES) respectively. Three-phased uncontrolled hemorrhagic shock and infection model was used. Phase I: Massive hemorrhage with a mean arterial pressure of 35-40 mmHg for 60 min, and followed by infection of lipopolysaccharide. Then some animals were resuscitated with solutions mentioned above, until 90 min. Phase II: At hemorrhagic shock 90 minutes, phase II of 60 minutes began with hemostasis and returning of all the initial shed blood. Phase III: Observation phase for 3.5 hours. After phase III, arterial blood gas analysis and the survival rates of the rats were recorded, Wet-to-dry lung weight ratio, BALF protein, pulmonary permeability index, and expressions of aquaporin1 and aquaporin5 were tested. RESULTS: The expressions of aquaporin1 and aquaporin5 were decreased in treatment groups comparing with sham operation group. Group HES and Group HTS decreased pulmonary vascular permeability and Wet-to-dry lung weight ratio, improved arterial blood gas analysis and survival rates, and attenuated the decreased pulmonary expression of aquaporin1 and aquaporin5 after the "two-hit", comparing with groups NF and LR,but these beneficial effects were blunted in group HTS. CONCLUSION: The expression of aquaporin1 and aquaporin5 may play important roles in formation of pulmonary edema. Resuscitation with HTS and HES, especially HES can reduce lung injury after hemorrhagic shock, partly by up-regulating the expressions of aquaporin1 and aquaporin5.

Heterochronic spontaneous rupture of bilateral renal cell carcinomas in a hemodialysis patient.

A 64-year-old man undergoing chronic hemodialysis was admitted under a shock state with macrohematuria and fatigue lasting for two hours. A blood analysis revealed severe anemia. Computed tomography disclosed a large right-sided perirenal hematoma. The patient was successfully treated with radical nephrectomy, leading to a histological diagnosis of spontaneous rupture of renal cell carcinoma (RCC). One year after rupture of the right RCC, he again developed macrohematuria and computed tomography revealed a left-sided perirenal hematoma. Radical nephrectomy followed by a histological examination revealed spontaneous rupture of the left-sided RCC. This case emphasizes the importance of conducting periodic imaging evaluations of chronic hemodialysis patients with renal cystic masses.

Reversal of dabigatran-induced bleeding with a prothrombin complex concentrate and fresh frozen plasma.

PURPOSE: The case of a patient for whom reversal of dabigatran-induced bleeding was performed with a prothrombin complex concentrate (PCC) and fresh frozen plasma (FFP) is reported. SUMMARY: An 85-year-old man arrived at the emergency department with complaints of generalized weakness, fatigue, and one episode of dark stool. The patient's medical history included hypertension, heart failure, stage III chronic kidney disease, cerebrovascular accident, prostate cancer, gastritis, esophagitis, diverticulosis, and a bleeding gastrointestinal ulcer. Laboratory test results revealed acute liver failure, acute kidney injury, and anemia. He was diagnosed with hemorrhagic shock secondary to bleeding in his upper gastrointestinal tract. A reversal strategy was implemented using 16 units of FFP and 2000 units of a three-factor PCC. After administration of these agents, the patient's hemoglobin concentration stabilized, and there were no further signs of overt bleeding, suggesting potential hemostasis. Confirmation of this reversal was not possible due to the effect of concomitant liver failure on the International Normalized Ratio and the activated partial thromboplastin time (aPTT), common variables used to measure coagulation. CONCLUSION: Treatment with a PCC and FFP was administered to an 85-year-old man diagnosed with hemorrhagic shock secondary to bleeding in his upper gastrointestinal tract in an effort to reverse the anticoagulant effects of dabigatran. Although the patient's hemoglobin levels stabilized and his aPTT values decreased after treatment, he died as a result of multiorgan failure.

Platonin mitigates lung injury in a two-hit model of hemorrhage/resuscitation and endotoxemia in rats.

BACKGROUND: Traumatic hemorrhagic shock and subsequent resuscitation may promote bacteria translocation and cause endotoxemia, a two-hit process that will induce severe lung injury. The pathogenesis involves oxidative stress, neutrophil infiltration, and inflammatory response. Platonin, a potent antioxidant, possesses potent anti-inflammation capacity. We sought to elucidate whether platonin could mitigate acute lung injury in a two-hit model of traumatic hemorrhage/resuscitation and subsequent endotoxemia. METHODS: Adult male rats were randomized to receive traumatic hemorrhage/resuscitation plus lipopolysaccharide (HS/L) alone or HS/L plus platonin (200 µg/kg; n = 12 in each group). Sham groups were used simultaneously. At 6 hours after resuscitation, rats were killed and the levels of lung injury were assayed. RESULTS: Rats treated with HS/L alone had severe lung injury as evidenced by significant alterations in lung function (i.e., arterial blood gas and alveolar-arterial oxygen difference) and histology. Significant increases in polymorphonuclear leukocytes/alveoli ratio (neutrophil infiltration index) and significant increases in the concentrations of inflammatory molecules (including chemokine, cytokine, and prostaglandin E2) and malondialdehyde (lipid peroxidation index) revealed that HS/L caused significant oxidative stress, neutrophil infiltration, and inflammatory response in rat lungs. Moreover, our data revealed that the levels of functional and histologic alteration as well as polymorphonuclear leukocytes/alveoli ratio and the concentrations of inflammatory molecules and malondialdehyde in rats treated with HS/L plus platonin (200 µg/kg) were significantly lower than those treated with HR/L alone. CONCLUSIONS: Platonin mitigates lung injury in a two-hit model of traumatic hemorrhage/resuscitation and endotoxemia in rats.

Immune safety evaluation of polymerized porcine hemoglobin (pPolyHb): a potential red blood cell substitute.

Polymerized Porcine Hemoglobin (pPolyHb), a hemoglobin-based oxygen carrier (HBOC), was developed as a potential red blood substitute for clinical applications. Assessment of its effects on the immune system is an important component of the overall safety evaluation of HBOC. For this purpose, we assessed three inflammation indicators, including complement C3a, IL-6, and TNF-? in cultured cells and in a rat model when pPolyHb was incubated or administrated with the cells/animals. Our results suggested that the levels of these three indicators were not statistically changed upon pPolyHb stimulation, indicating that pPolyHb is not immunotoxic to cells and animals in this aspect.

Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock.

OBJECTIVE: Intravenous infusion of crystalloid solutions is a cornerstone of the treatment of hemorrhagic shock. However, crystalloid solutions can have variable metabolic acid-base effects, perpetuating or even aggravating shock-induced metabolic acidosis. The aim of this study was to compare, in a controlled volume-driven porcine model of hemorrhagic shock, the effects of three different crystalloid solutions on the hemodynamics and acid-base balance. METHODS: Controlled hemorrhagic shock (40% of the total blood volume was removed) was induced in 18 animals, which were then treated with normal saline (0.9% NaCl), Lactated Ringer's Solution or Plasma-Lyte pH 7.4, in a blinded fashion (n = 6 for each group). Using a predefined protocol, the animals received three times the volume of blood removed. RESULTS: The three different crystalloid infusions were equally capable of reversing the hemorrhage-induced low cardiac output and anuria. The Lactated Ringer's Solution and Plasma-Lyte pH 7.4 infusions resulted in an increased standard base excess and a decreased serum chloride level, whereas treatment with normal saline resulted in a decreased standard base excess and an increased serum chloride level. The Plasma-Lyte pH 7.4 infusions did not change the level of the unmeasured anions. CONCLUSION: Although the three tested crystalloid solutions were equally able to attenuate the hemodynamic and tissue perfusion disturbances, only the normal saline induced hyperchloremia and metabolic acidosis.

Identification of citrullinated histone H3 as a potential serum protein biomarker in a lethal model of lipopolysaccharide-induced shock.

BACKGROUND: Circulating proteins may serve as biomarkers for the early diagnosis and treatment of shock. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced septic shock. Preliminary proteomic data showed that LPS-induced shock altered a number of proteins in circulation, including histone H3 (H3) and citrullinated histone H3 (Cit H3). The present study was designed to confirm these findings and to test whether the pro-survival phenotype could be detected by an early alteration in serum biomarkers. METHODS: Three experiments were performed. In experiment I, Western blotting was performed on serum samples from male C57B1/6J mice (n = 9, 3/group) that belonged to the following groups: (a) LPS (20 mg/kg)-induced septic shock, (b) SAHA-treated septic shock, and (c) sham (no LPS, no SAHA). In experiment II, HL-60 granulocytes were cultured and treated with LPS (100 ng/m1) in the absence or presence of SAHA (10 µmol/L). Sham (no LPS, no SAHA) granulocytes served as controls. The medium and cells were harvested at 3 hours, and proteins were measured with Western blots. In experiment III, a large dose (LD, 35 mg/kg) or small dose (SD, 10 mg/kg) of LPS was injected intraperitoneally into the C57B1/6J mice (n = 10 per group). Blood was collected at 3 hours, and serum proteins were determined by Western blots or enzyme-linked immunosorbent assay (ELISA). All of the Western blots were performed with antibodies against H3, Cit H3, and acetylated H3 (Ac H3). ELISA was performed with antibody against tumor necrosis factor (TNF)-α. Survival rates were recorded over 7 days. RESULTS: In experiment I, intraperitoneal (IP) injection of LPS (20 mg/kg) significantly increased serum levels of H3, which was prevented by SAHA treatment. In experiment II, LPS (100 ng/mL) induced expression and secretion of Cit H3 and H3 proteins in neutrophilic HL-60 cells, which was decreased by SAHA treatment. In experiment III, administration of LPS (LD) caused a rise in serum H3 and Cit H3 but not Ac H3 at 3 hours, and all of these animals died within 23 hours (100% mortality). Decreasing the dose of LPS (SD) significantly reduced the mortality rate (10% mortality) as well as the circulating levels of Cit H3 (non detectable) and H3. An increase in serum TNF-α was found in both LPS (LD) and (SD) groups, but in a non-dose-dependent fashion. CONCLUSION: Our results reveal for the first time that Cit H3 is released into circulation during the early stages of LPS-induced shock. Moreover, serum levels of Cit H3 are significantly associated with severity of LPS-induced shock. Therefore, Cit H3 could serve as a potential protein biomarker for early diagnosis of septic shock, and for predicting its lethality.

Impact of Plasma-Lyte pH 7.4 on acid-base status and hemodynamics in a model of controlled hemorrhagic shock

OBJECTIVE: Intravenous infusion of crystalloid solutions is a cornerstone of the treatment of hemorrhagic shock. However, crystalloid solutions can have variable metabolic acid-base effects, perpetuating or even aggravating shock-induced metabolic acidosis. The aim of this study was to compare, in a controlled volume-driven porcine model of hemorrhagic shock, the effects of three different crystalloid solutions on the hemodynamics and acid-base balance. METHODS: Controlled hemorrhagic shock (40 percent of the total blood volume was removed) was induced in 18 animals, which were then treated with normal saline (0.9 percent NaCl), Lactated Ringer's Solution or Plasma-Lyte pH 7.4, in a blinded fashion (n = 6 for each group). Using a predefined protocol, the animals received three times the volume of blood removed. RESULTS: The three different crystalloid infusions were equally capable of reversing the hemorrhage-induced low cardiac output and anuria. The Lactated Ringer's Solution and Plasma-Lyte pH 7.4 infusions resulted in an increased standard base excess and a decreased serum chloride level, whereas treatment with normal saline resulted in a decreased standard base excess and an increased serum chloride level. The Plasma-Lyte pH 7.4 infusions did not change the level of the unmeasured anions. CONCLUSION: Although the three tested crystalloid solutions were equally able to attenuate the hemodynamic and tissue perfusion disturbances, only the normal saline induced hyperchloremia and metabolic acidosis.

Cardiocirculatory changes in hemorrhagic shock induced in pigs submitted to three distinct therapeutic methods.

PURPOSE: To evaluate and compare the response of pigs submitted to hemorrhagic shock and treated using three different strategies. METHODS: Thirty-five Dalland pigs were divided into four groups: Control; Bleeding; Saline and Saline + Red Cell Concentrate. Parameters evaluated: heart rate (HR), mean arterial blood pressure (MAP) and central vein pressure (CVP).Hemorrhagic shock was induced by removing (624.25 + or - 64.55), (619.30 + or - 44.94) and (664.23 + or - 39.96) ml of blood respectively, with the following treatment: Bleeding Group - zero volume replacement; Saline Group - replacement with 676 ml of 0.9% saline solution; Saline + Red Cell Concentrate Group - replacement with 440 ml of 0.9% saline solution + 291 ml of red cell concentrate. The treatment was evaluated after 10 (T3), 30 (T4), 45 (T5) and 60 (T6) minutes. RESULTS: HR: No statistically significant difference was found between the Bleeding and Saline [p=1.000], Bleeding and Saline + Red Cell Concentrate [p=1.000], and Saline and Saline + Red Cell Concentrate [p=0.721] groups. MAP; Significant differences were found between all the groups studied. CVP: No significant difference was found between the groups. CONCLUSION: Non-replacement and euvolemic resuscitation maintained a satisfactory hemodynamic pattern in controlled severe hemorrhagic shock in swine. The euvolemic replacement strategies exceeded the limit values of MAP for rebleeding.