A Multifunctional, Low-Volume Resuscitation Cocktail Improves Vital Organ Blood Flow and Hemostasis in a Pig Model of Polytrauma with Traumatic Brain Injury

The resuscitation of polytrauma with hemorrhagic shock and traumatic brain injury (TBI) is a balance between permissive hypotension and maintaining vital organ perfusion. There is no current optimal solution. This study tested whether a multifunctional resuscitation cocktail supporting hemostasis and perfusion could mitigate blood loss while improving vital organ blood flow during prolonged limited resuscitation. Anesthetized Yorkshire swine were subjected to fluid percussion TBI, femur fracture, catheter hemorrhage, and aortic tear. Fluid resuscitation was started when lactate concentration reached 3–4 mmol/L. Animals were randomized to one of five groups. All groups received hydroxyethyl starch solution and vasopressin. Low- and high-dose fibrinogen (FBG) groups additionally received 100 and 200 mg/kg FBG, respectively. A third group received TXA and low-dose FBG. Two control groups received albumin, with one also including TXA. Animals were monitored for up to 6 h. Blood loss was decreased and vital organ blood flow was improved with low- and high-dose fibrinogen compared to albumin controls, but survival was not improved. There was no additional benefit of high- vs. low-dose FBG on blood loss or survival. TXA alone decreased blood loss but had no effect on survival, and combining TXA with FBG provided no additional benefit. Pooled analysis of all groups containing fibrinogen vs. albumin controls found improved survival, decreased blood loss, and improved vital organ blood flow with fibrinogen delivery. In conclusion, a low-volume resuscitation cocktail consisting of hydroxyethyl starch, vasopressin, and fibrinogen concentrate improved outcomes compare to controls during limited resuscitation of polytrauma.

Rewarming With Closed Thoracic Lavage Following 3-h CPR at 27°C Failed to Reestablish a Perfusing Rhythm

Introduction: Previously, we showed that the cardiopulmonary resuscitation (CPR) for hypothermic cardiac arrest (HCA) maintained cardiac output (CO) and mean arterial pressure (MAP) to the same reduced level during normothermia (38°C) vs. hypothermia (27°C). In addition, at 27°C, the CPR for 3-h provided global O2 delivery (DO2) to support aerobic metabolism. The present study investigated if rewarming with closed thoracic lavage induces a perfusing rhythm after 3-h continuous CPR at 27°C.Materials and Methods: Eight male pigs were anesthetized, and immersion-cooled. At 27°C, HCA was electrically induced, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed by combining closed thoracic lavage and continued CPR. Organ blood flow was measured using microspheres.Results: After cooling with spontaneous circulation to 27°C, MAP and CO were initially reduced by 37 and 58% from baseline, respectively. By 15 min after the onset of CPR, MAP, and CO were further reduced by 58 and 77% from baseline, respectively, which remained unchanged throughout the rest of the 3-h period of CPR. During CPR at 27°C, DO2 and O2 extraction rate (VO2) fell to critically low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. During rewarming with closed thoracic lavage, all animals displayed ventricular fibrillation, but only one animal could be electro-converted to restore a short-lived perfusing rhythm. Rewarming ended in circulatory collapse in all the animals at 38°C.Conclusion: The CPR for 3-h at 27°C managed to sustain lower levels of CO and MAP sufficient to support global DO2. Rewarming accidental hypothermia patients following prolonged CPR for HCA with closed thoracic lavage is not an alternative to rewarming by extra-corporeal life support as these patients are often in need of massive cardio-pulmonary support during as well as after rewarming.

Effects of rewarming with extracorporeal membrane oxygenation to restore oxygen transport and organ blood flow after hypothermic cardiac arrest in a porcine model

We recently documented that cardiopulmonary resuscitation (CPR) generates the same level of cardiac output (CO) and mean arterial pressure (MAP) during both normothermia (38 °C) and hypothermia (27 °C). Furthermore, continuous CPR at 27 °C provides O2 delivery (ḊO2) to support aerobic metabolism throughout a 3-h period. The aim of the present study was to investigate the effects of extracorporeal membrane oxygenation (ECMO) rewarming to restore ḊO2 and organ blood flow after prolonged hypothermic cardiac arrest. Eight male pigs were anesthetized and immersion cooled to 27 °C. After induction of hypothermic cardiac arrest, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed with ECMO. Organ blood flow was measured using microspheres. After cooling with spontaneous circulation to 27 °C, MAP and CO were initially reduced to 66 and 44% of baseline, respectively. By 15 min after the onset of CPR, there was a further reduction in MAP and CO to 42 and 25% of baseline, respectively, which remained unchanged throughout the rest of 3-h CPR. During CPR, ḊO2 and O2 uptake (V̇O2) fell to critical low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. Rewarming with ECMO restored MAP, CO, ḊO2, and blood flow to the heart and to parts of the brain, whereas flow to kidneys, stomach, liver and spleen remained significantly reduced. CPR for 3-h at 27 °C with sustained lower levels of CO and MAP maintained aerobic metabolism sufficient to support ḊO2. Rewarming with ECMO restores blood flow to the heart and brain, and creates a “shockable” cardiac rhythm. Thus, like continuous CPR, ECMO rewarming plays a crucial role in “the chain of survival” when resuscitating victims of hypothermic cardiac arrest.

A Population Physiologically‐Based Pharmacokinetic Model to Characterize Antibody Disposition in Pediatrics and Evaluation of the Model using Infliximab

Aims: In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in pediatric patients, there is a need to develop systems PK models that integrate ontogeny related changes in human physiological parameters. Methods: A population-based physiological-based PK (PBPK) model to characterize antibody PK in pediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate, and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose-exposure relationship for infliximab. Results: By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two pediatric cohorts (n=141, 4-19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. Conclusion: The pediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in pediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.

Effects of Rewarming with Extracorporeal Membrane Oxygenation to Restore Oxygen Transport and Organ Blood Flow After Hypothermic Cardiac Arrest in a Porcine Model.

Background: We recently documented that cardiopulmonary resuscitation (CPR) for hypothermic cardiac arrest maintains cardiac output (CO) and mean arterial pressure (MAP) to the same reduced level during normothermia (38°C) vs. hypothermia (27°C). Furthermore, continuous CPR at 27°C maintains CO and MAP throughout a 3-h period, and provides O2 delivery to support aerobic metabolism. The aim of the present study was to investigate the effects of extracorporeal membrane oxygenation (ECMO) rewarming to restore O2 delivery and organ blood flow. Methods: Eight male pigs were anesthetized and immersion cooled to 27°C. After induction of hypothermic cardiac arrest, CPR was started and continued for a 3-h period. Thereafter, the animals were rewarmed with ECMO. Organ blood flow was measured using microspheres. Results: After cooling with spontaneous circulation to 27°C, MAP and CO were initially reduced to 66 and 44% of baseline, respectively. By 15 min after the onset of CPR, there was a further reduction in MAP and CO to 42 and 25% of baseline, respectively, which remained unchanged throughout the rest of 3-h CPR. During CPR, O2 delivery and O2 uptake (V̇O2) fell to critical low levels, but the simultaneous small increase in lactate and a modest reduction in pH, indicated the presence of maintained aerobic metabolism. Rewarming with ECMO restored MAP, CO, O2 delivery, and blood flow to the heart and to parts of the brain, whereas flow to kidneys, stomach, liver and spleen remained significantly reduced. Conclusions: CPR for 3-h at 27°C with sustained lower levels of CO and MAP and maintained aerobic metabolism sufficient to support O2 delivery. Rewarming with ECMO restores blood flow to the heart and brain, and creates a “shockable” cardiac rhythm. Thus, like continuous CPR, ECMO rewarming plays a crucial role in “the chain of survival” when resuscitating victims of hypothermic cardiac arrest.

The basal release of endothelium-derived catecholamines regulates the contractions of Chelonoidis carbonaria aorta caused by electrical-field stimulation

The contractions of Chelonoidis carbonaria aortic rings induced by electrical field stimulation (EFS) are not inhibited by blockade of the voltage-gated sodium channels by tetrodotoxin but almost abolished by the α1/α2-adrenoceptor antagonist phentolamine. The objective of this study was to identify the mediator(s) responsible for the EFS-induced contractions of Chelonoidis carbonaria aortic rings. Each ring was suspended between two wire hooks and mounted in isolated 10 mL organ chambers filled with oxygenated and heated Krebs-Henseleit's solution. Dopamine, noradrenaline and adrenaline concentrations were analysed by liquid chromatography coupled to tandem mass spectrometry. The contractions caused by dopamine and EFS were done in absence and presence of the nitric oxide (NO) synthesis inhibitor L-NAME, the NO-sensitive guanylyl cyclase inhibitor ODQ, the D1-like receptor antagonist SCH-23390, the D2-like receptor antagonists risperidone, quetiapine, haloperidol, and the tyrosine hydroxylase inhibitors salsolinol and 3-iodo-L-tyrosine. Basal concentrations of dopamine, noradrenaline and adrenaline were detected in Krebs-Henseleit solution containing the aortic rings. The catecholamine concentrations were significantly reduced in endothelium-denuded aortic rings. L-NAME and ODQ significantly potentiated the dopamine-induced contractions. The D2-like receptor antagonists inhibited the EFS-induced contractions of the aortic rings treated with L-NAME, whereas SCH 23390 had no effect. Similar results were observed in the contractions induced by dopamine in L-NAME treated aortic rings. These results indicate that catecholamines released by endothelium regulate the EFS-induced contractions. This may constitute a suitable mechanism by which reptilia modulate specific organ blood flow distribution.

Ultrasonic characteristic of the liver in early congenital syphilis in children

Introduction. Liver lesion in congenital syphilis in infants in the first months of life is clinically observed in 74–86% of children in the form of enlargement and thickening during palpation. Pathological and anatomical studies reveal in 100% of cases typical changes in the liver, which are mainly due to diffuse round-cell infiltration, expansion of connective tissue and formation of gummas. Purpose of research. To analyze the indicators of ultrasound examination of the liver and spleen with the assessment of organ blood flow in children born to women with syphilitic infection and to identify the most significant signs associated with early congenital syphilis in the neonatal period.Materials and methods. The paper analyzes the data of a comprehensive survey of 397 newborns who were under observation from birth to 1 month of life, included in the study with the indication of the fact, born to women with a history of documented confirmed syphilitic infection.On the basis of the total sample, three groups of children from birth to 28 days of life were formed, taking into account the Federal clinical guidelines for the management of patients with syphilis (Moscow, 2015).The results of the study and their discussion. In 1 and 2 study groups found a significant increase in the oblique vertical size of the right lobe was 74.3 ± 0.7 mm (p < 0.05) and 73.9 ± 0.4 mm (p < 0.05), vs. 68.8 ± 0.3 mm in the control, as well as the thickness of the left lobe of the liver is 35.3 ± 0.4 mm (p < 0.05) and 34.8 ± 0.6 mm (p < 0.05), compared to 31.4 ± 0.7 mm in the control group. Along with this, in these groups, a higher index of the maximum blood flow velocity in the portal vein was noted, which in these 1 and 2 groups was 0.26 ± 0.02 m/s (p < 0.05) and 0.25 ± 0.02 m/s (p < 0.05), respectively, against 0.20 ± 0.02 m/s in the control. Along with sonographic signs, there was a significant prevalence of hyperbilirubinemia in groups 1 and 2 of newborns – 24.1% (p < 0.001) and 19.9%, respectively, against 9.0% in the control group (neonatal hepatitis was diagnosed in 11.4% of newborns with early congenital syphilis).Conclusion. The ultrasound features of the liver and early congenital syphilis include an increase in size, structural changes in the liver (only in PBC with symptoms) and hemodynamic features, characterized by increased blood flow by increasing the absolute value of linear velocities (maximum systolic and minimum diastolic) with a reduced resistance index.

Duktus Arteriosus pada Bayi Prematur

Abstract—Ductus arteriosus (DA) is a connecting vessel between proximal descending aorta and pulmonary artery. This important structure normally close after birth. The opened ductus causes increasing of pulmonary blood flow and decreasing of certain organ blood flow (intestine, skin, muscle, and renal) causing complications such as heart failure, metabolic acidosis, necrotizing enterocolitis, and pulmonary edema/bleeding. Prevalence of DA is 0,2/1000 live birth. In under 1500 g babies the proportion of DA is 25%. Surgery and medicine are the treatment modalities of DA closure. Modalities of medicine are indometacine, ibuprofen, and paracetamol. These three modalities work by inhibiting cyclooxygenase enzime causing blockade of prostaglandin synthesis. Drug adverse event can be minimized by carefull in making treatment choice. Keywords: ductus arteriosus, complication, treatment Abstrak—Duktus arteriosus (DA) merupakan pembuluh darah yang menghubungkan aorta desendens proksimal dan arteri pulmonalis. Struktur yang penting pada janin tersebut secara normal menutup setelah lahir. Duktus yang masih terbuka tersebut mengakibatkan peningkatan aliran darah paru dan penurunan aliran darah ke organ usus, kulit, otot, dan ginjal sehingga menyebabkan komplikasi seperti gagal jantung, asidosis metabolik, necrotizing enterocolitis (NEC), serta edema paru/perdarahan. Prevalensi DA yang masih terbuka adalah 0,2 per 1000 kelahiran hidup. Proporsi bayi yang bergejala dengan DA yang masih terbuka kurang lebih 25% bayi dengan berat badan lahir di bawah 1500g. Pilihan terapi penutupan DA adalah cara bedah dan medis. Cara medis memiliki beberapa pilihan yaitu indometasin, ibuprofen, dan parasetamol. Ketiga modalitas terapi tersebut bekerja melalui penghambatan enzim siklooksigenase sehingga sintesis prostaglandin terhambat. Beberapa hal perlu diperhatikan dalam membuat pilihan terapi sehingga komplikasi yang berhubungan dengan efek samping obat dapat dihindari.. Kata kunci: ductus arteriosus, komplikasi, terapi

Biologic therapy in supra-aortic Takayasu arteritis can improve symptoms of cerebral ischaemia without surgical intervention

Objectives Takayasu arteritis commonly results in severe arterial injury with stenoses, occlusions and occasionally aneurysms. Arterial disease may compromise organ blood flow and result in significant cardiovascular morbidity and premature mortality. Involvement of the supra-aortic arteries is common, and in its most severe form may compromise cerebral blood supply, resulting in signs of cerebral ischaemia including visual impairment, dysphasia, transient hemiparesis, loss of consciousness and stroke. In addition to combination immunosuppression, the management paradigm for symptomatic cerebral ischaemia includes revascularization. The invasive nature of this surgery, the risk of complications and the relatively high rate of re-stenosis is of concern to patients and their physicians alike. The aim of this study was to determine whether combined immunosuppression with early escalation to biologic therapy improved outcomes and reduced the need for high risk surgical intervention. Methods A retrospective review of 145 Takayasu arteritis patients attending Imperial College Healthcare between 2010–2018 was conducted to identify those with cerebral ischaemia secondary to supra-aortic disease and to analyse their treatment and outcomes. Results Eight patients (5.5%) were identified. Seven patients received long-term combined immunosuppressive therapy and six were prescribed biologics. The data revealed a higher than expected comprehensive response to therapy, with significant falls in disease activity, the cerebral ischaemia score and the prednisolone dose required, over a median follow-up of 37 months. Serial imaging analysis detected no arterial disease progression after the initiation of optimal therapy. Only one patient required surgical intervention for persistent neurological symptoms. Conclusion Early use of biologic therapy in those with supra-aortic Takayasu arteritis presenting with cerebral ischaemia may reduce the numbers of patients requiring surgical intervention and improve outcomes.