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Most U.S. overnight youth camps did not operate during the summer of 2020 because of the COVID-19 pandemic* (1). Several that did operate demonstrated that multiple prevention strategies, including pre- and postarrival testing for SARS-CoV-2, the virus that causes COVID-19, masking, and physical distancing helped prevent the introduction and spread of COVID-19; in contrast, camps that relaxed prevention strategies, such as requiring a single prearrival test without subsequent testing, experienced outbreaks (2-4). The availability of COVID-19 vaccines for persons aged ≥12 years enabled implementation of an additional prevention strategy that was not available in summer 2020. This study assessed the number of COVID-19 cases and potential secondary spread among 7,173 staff members and campers from 50 states, 13 countries, and U.S. military overseas bases at nine independently operated U.S. summer youth camps affiliated with the same organization. The camps implemented multiple prevention strategies including vaccination, testing, podding (cohorting), masking, physical distancing, and hand hygiene during June-August 2021. Vaccination coverage was 93% among eligible persons aged ≥12 years.† All staff members (1,955) and campers (5,218) received site-specific, protocol-defined screening testing, which included prearrival testing and screening tests during the camp session (38,059 tests). Screening testing identified six confirmed COVID-19 cases (one in a staff member and five in campers) by reverse transcription-polymerase chain reaction (RT-PCR) testing (screening test positivity rate = 0.02%). Three additional cases (in two staff members and one camper) were identified based on symptoms and were confirmed by RT-PCR testing. Testing for SARS-CoV-2, isolation, and quarantine in a population with high vaccination coverage resulted in no known secondary transmission of SARS-CoV-2 identified during camp. Implementation of multicomponent strategies is critical for prevention of COVID-19 outbreaks in congregate settings, including overnight youth camps.

Objectives Characterize transport medical control education in Pediatric Critical Care Medicine fellowship. Design Cross-sectional survey study. Setting Pediatric Critical Care Medicine fellowship programs in the United States. Subjects Pediatric Critical Care Medicine fellowship program directors. Interventions None. Measurements and main results We achieved a 74% (53/72) response rate. A majority of programs (85%) require fellows to serve as transport medical control, usually while carrying out other clinical responsibilities and sometimes without supervision. Fellows at most programs (80%) also accompany the transport team on patient retrievals. Most respondents (72%) reported formalized transport medical control teaching, primarily in a didactic format (76%). Few programs (25%) use a standardized assessment tool. Transport medical control was identified as requiring all six Accreditation Council for Graduate Medical Education competencies, with emphasis on professionalism and interpersonal and communication skills. Conclusions Transport medical control responsibilities are common for Pediatric Critical Care Medicine fellows, but training is inconsistent, assessment is not standardized, and supervision may be lacking. Fellow performance in transport medical control may help inform assessment in multiple domains of competencies. Further study is needed to identify effective methods for transport medical control education.

The Transport Risk Assessment in Pediatrics (TRAP) and Transport Pediatric Early Warning Scores (T-PEWS) are transport-specific pediatric illness severity scores that are adjunct assessment tools for determining disposition of transported patients. We hypothesized that these scores would predict the risk of clinical deterioration in transported patients admitted to general pediatric wards.Activation of a rapid response team (RRT) in the first 24 hours of admission was used as a marker of deterioration. All pediatric transports between March 2017 and February 2020 admitted via critical care transport were included. Transports to the emergency department (ED) were excluded. This retrospective chart review evaluated TRAP and T-PEWS scores at 3 points: (1) arrival of transport team at referring hospital, (2) admission to the children's hospital, and (3) RRT activation, if occurring within 24 hours of admission.There were 1137 team transports during this period. Three hundred ninety-nine patients transported to the ED were excluded, leaving 738 included patients; 405 (55%) admitted to the general wards and 333 (45%) admitted to the pediatric intensive care unit. Twenty-five patients admitted to the wards (6%) had an RRT activation within 24 hours of admission. Statistical analysis used 2-sample t tests. There was a statistically significant difference in scores for ward admissions between those who had RRT activation and those who did not.Both TRAP and T-PEWS can be used to predict the risk of clinical deterioration in transported patients admitted to general wards. These scores may assist in assessing which patients admitted to the wards need closer observation.

To determine whether the receipt of more than or equal to 30 mL/kg of intravenous fluid in the first hour after emergency department (ED) arrival is associated with sepsis-attributable mortality among children with hypotensive septic shock.This is a retrospective cohort study set in 57 EDs in the Improving Pediatric Sepsis Outcomes quality improvement collaborative. Patients less than 18 years of age with hypotensive septic shock who received their first intravenous fluid bolus within 1 hour of arrival at the ED were propensity-score matched for probability of receiving more than or equal to 30 mL/kg in the first hour. Sepsis-attributable mortality was compared. We secondarily evaluated the association between the first-hour fluid volume and sepsis-attributable mortality in all children with suspected sepsis in the first hour after arrival at the ED, regardless of blood pressure.Of the 1,982 subjects who had hypotensive septic shock and received a first fluid bolus within 1 hour of arrival at the ED, 1,204 subjects were propensity matched. In the matched patients receiving more than or equal to 30 mL/kg of fluid, 26 (4.3%) of 602 subjects had 30-day sepsis-attributable mortality compared with 25 (4.2%) of 602 receiving less than 30 mL/kg (odds ratio 1.04, 95% confidence interval 0.59 to 1.83). Among the patients with suspected sepsis regardless of blood pressure, 30-day sepsis-attributable mortality was 3.0% in those receiving more than or equal to 30 mL/kg versus 2.0% in those receiving less than 30 ml/kg (odds ratio 1.52, 95% confidence interval 0.95 to 2.44.) CONCLUSION: In children with hypotensive septic shock receiving a timely first fluid bolus within the first hour of ED care, receiving more than or equal to 30 mL/kg of bolus intravenous fluids in the first hour after arrival at the ED was not associated with mortality compared with receiving less than 30 mL/kg.

This case report describes new-onset adrenal insufficiency and adrenal shock in an 11-year-old male complaining of two weeks of malaise and weight loss. He was lethargic and pale in appearance. Work-up revealed hypoglycemia and hyponatremia without evidence for an infectious process. He was transported via a pediatric critical care transport team to a regional pediatric intensive care unit (PICU). He required intravenous fluids and vasopressors prior to arrival in the PICU. He had generalized weakness, and hyperpigmentation of his face and extremities. Adrenal insufficiency was suspected, and glucocorticoid administration led to improvement. Cortisol level was undetectable. At time of discharge, he was prescribed daily glucocorticoid and mineralocorticoid replacement, along with a stress dose glucocorticoid plan.

Interfacility transport of critically ill infants and children is an essential part of the care of children in the United States. However, there is tremendous variation in how transports are coordinated and performed. Pediatric critical care medicine (PCCM) fellows have differing experiences in their fellowships, and there is no standardized way of training medical command for the transport process. The aim of this study was to use a consensus-building process to establish core components of a PCCM transport curriculum focused on communication.A national group of experts in transport medicine rated 51 total possible topics for their importance to include in a fellowship curriculum. Three rounds of surveys were completed.Fifty-two of 372 invitees (14%) participated in round 1. Consensus was reached to include 15 items in a PCCM curriculum. Twenty of 52 (38%) experts completed round 2, reaching consensus on 2 additional items. Seventeen of 20 (85%) experts completed round 3. No additional items reached consensus.Experts reached consensus on 17 core components to include in a PCCM fellowship transport communication curriculum. This curriculum could likely be adapted to train providers from different disciplines in the transport process.

Objective The coronavirus disease 2019 (COVID-19) pandemic has altered the provision of health care, including interfacility transport of critically ill neonatal and pediatrics patients. Transport medicine faces unique challenges in the care of persons infected with the severe acute respiratory syndrome coronavirus 2. In particular, the multitude of providers, confined spaces for prolonged time periods, varying modes (ground, rotor wing, and fixed wing) of transport, and the need for frequent aerosol-generating procedures place transport personnel at high risk. This study describes the clinical practices, personal protective equipment, and potential exposure risks of a large cohort of neonatal and pediatric interfacility transport teams. Methods Data for this study came from a survey distributed to members of the American Academy of Pediatrics Section on Transport Medicine. Results Fifty-four teams responded, and 47 reported transporting COVID-19–positive patients. Among the 47 teams, 25% indicated having at least 1 team member convert to COVID-19 positive. A small percentage of teams (40% ground, 40% fixed wing, and 18% rotor wing) reported allowing parental accompaniment during transport. There was no difference in teams with a positive team member among those that do (26%) and do not (25%) allow parents. There was a higher percentage of teams with a positive team member among teams that intubate (32% vs. 0%) and place laryngeal mask airways (34% vs. 0%) during transport. Conclusion Our study shows that exceptional care during interfacility transport, including a family-centered approach, can continue during the COVID-19 pandemic. Teams must take steps to protect themselves, as well as the patients and families they serve, in order to mitigate the transmission of the SARS-CoV-2 virus.

Introduction: The Transport Pediatric Early Warning Scores (TPEWS) and Transport Risk Assessment in Pediatrics (TRAP) scores are transport medicine-specific illness severity scores that are adjunct assessment tools for determining patient disposition. We hypothesized that these scores would predict acuity and risk of clinical deterioration in transported patients admitted to general pediatric wards. We utilized activation of a rapid response team (RRT) in the first 24 hours of admission as a marker of deterioration. Methods: We reviewed all pediatric transports admitted via our pediatric critical care transport team to our tertiary care children’s hospital wards or PICU from July 1, 2018-June 30, 2019. Patients …

Objectives:The American College of Critical Care Medicine provided 2002 and 2007 guidelines for hemodynamic support of newborn and pediatric septic shock. Provide the 2014 update of the 2007 American College of Critical Care Medicine “Clinical Guidelines for Hemodynamic Support of Neonates and Child

Introduction: The risk of lights and sirens use in emergency medical services has been well documented. Our critical care transport team performs over 1,800 interfacility nonemergency medical services transports annually into a dense urban environment. Historically, we have utilized lights and sirens to navigate traffic patterns. The use exceeded industry standards. This quality improvement project was undertaken to decrease the use of lights and sirens. Methods/Results: The baseline use of lights and sirens in 2011 was 76% en route and 73% on return to the facility. We revised the internal policy guiding the appropriate usage of lights and sirens. In 2012, without an improvement in usage, a use justification process was implemented. By 2013, the use of lights and sirens was still high en route, but had decreased to 53% on the return trip. In 2014, we added accountability measures requiring justification, with a subsequent drop in 2015 to 14% en route and 13% on return. In the following 3 years, the transport teams have sustained lights and sirens use to 20% or below. Conclusions: This quality improvement initiative impacted team behavior and decreased the use of lights and sirens over 5 years, with sustained improvement at or below 20%. This improvement was accomplished through ongoing evaluation, education, data gathering, and open communication. There was no negative impact on patient outcomes during this time. Lights and sirens continue to be used when indicated.

ObjectivesOur institution relocated to a new facility 3.5 miles from our original location in Chicago on June 9, 2012. We describe the tools we developed to prepare, execute, and manage our evacuation and relocation.MethodsTools developed for the planned evacuation included the following: level of acuity and team composition classification, patient departure checklist, evacuation handoff tool, and a patient tracking system within the electronic health record. Incident Command structure was utilized.ResultsMonthly census tracking exercises were held beginning 12 months before the evacuation. Simulation drills began 6 months before the evacuation. The entire evacuation took less than 14 hours and there were no safety issues. A total of 127 patients were transported to the new facility: 45 patients were moved via the Neonatal/Pediatric Critical Care Transport Team, and the rest were moved with various team configurations.ConclusionDocuments developed for a planned evacuation can be used for any planned or unplanned evacuation. We believe the tools we used to prepare, execute, and manage our evacuation and relocation would assist any health care facility to be better prepared to safely and efficiently evacuate patients in the event of a disaster, or to create surge capacity, and relocate them to another facility. (Disaster Med Public Health Preparedness. 2017;11:479–486)

Sepsis is a leading cause of morbidity and mortality in critically ill pediatric patients. The early diagnosis of sepsis is often difficult. Clinical signs and symptoms consistent with established criteria often occur late in the course of illness. In addition, early manifestations of sepsis are often nonspecific and can occur in many other disease processes, which confound the clinical picture. Therefore, identifying markers that are both sensitive and specific would be extremely helpful to the clinician for definitive diagnosis of sepsis before progression to severe disease. The purpose of this review is to describe the more common physiomarkers and biomarkers used that may aid in the diagnosis of sepsis as well as describe promising biomarkers that may be more widely available in the future.

Objective To assess health-care teams' verbal communication, an observable teamwork behavior, during simulations involving pediatric emergency airway management and intubation. Methods We conducted video-recorded, risk-informed in situ simulations at 5 hospitals with pediatric intensive care units in the Chicago, Illinois, area. Clinicians participated in their clinical roles (eg, attending physician, bedside nurse) and had access to hospital operational systems (eg, electronic health record, medical imaging, laboratory services). Video-recordings were transcribed; 3 pediatric critical care physicians analyzed the transcripts to assess preintubation communication: (a) the declaration of an airway emergency, (b) intubation medication request(s), and (c) preintubation medication administration. Results Ten pediatric intensive care unit simulations were analyzed. Statements to notify the care team of an airway emergency varied widely. In 3 simulations, a dosage for every medication was verbalized in the physician's initial medication request; however, in 4 simulations, a nurse was the first to verbalize the medication dosage(s) before administration. In 6 of the simulations where preintubation medications were administered, multiple requests for medications were verbalized. A clinician verbally confirmed that each medication was administered in only 2 of the simulations. Conclusions No uniform statement was identified to declare an airway emergency among the care teams. Preintubation medication dosages were not consistently included in intubation medication orders, and frequently, there were multiple requests to obtain medications. Using standardized language to declare an airway emergency and verbally communicating medication requests and dosages and confirming administration may improve the quality of care in this critical event.

Interfacility transport of critically ill pediatric patients requires coordination among referring physicians/institutions, receiving physicians/institutions, transport team personnel, and emergency medical services. Specialized transport teams can facilitate these transports as well as provide a unique service to the patients and their families. Providing critical care to patients in a transport environment is very different from providing this care in the intensive care unit or the emergency department. Transport personnel must be trained and equipped to provide this care in various environments, including ambulance, rotor wing, and fixed wing aircraft. This article reviews the process of setting up a pediatric critical care transport, team composition, equipment needs, personnel requirements, safety issues, and legal issues related to the interfacility transport of pediatric patients.

Bacterial endotoxin (lipopolysaccharide; LPS) and platelet-activating factor (PAF) are important triggers of bowel inflammation and injury. We have previously shown that LPS activates the transcription factor nuclear factor (NF)-kappaB in the intestine, which up-regulates many pro-inflammatory genes. This effect partly depends on neutrophils and endogenous PAF. However, whether LPS and PAF directly activate NF-kappaB in enterocytes remains controversial. In this study, we first investigated the effect of LPS and PAF on NF-kappaB activation in IEC-6 (a non-transformed rat small intestinal crypt cell line) cells, by electrophoresis mobility shift assay and supershift, and found that LPS, but not PAF, activates NF-kappaB mostly as p50-p65 heterodimers. The effect was slower than tumour necrosis factor (TNF). Both LPS and TNF induce the expression of the NF-kappaB-dependent gene inducible nitric oxide synthase (iNOS), which occurs subsequent to NF-kappaB activation. We then examined the effect of LPS and TNF on the inhibitory molecules IkappaBalpha and IkappaBbeta. We found that TNF causes rapid degradation of IkappaBalpha and IkappaBbeta. In contrast, LPS did not change the levels of IkappaBalpha and IkappaBbeta up to 4 hr (by Western blot). However, in the presence of cycloheximide, there was a slow reduction of IkappaBalpha and IkappaBbeta, which disappeared almost completely at 4 hr. These observations suggest that LPS causes slow degradation and synthesis of IkappaBalpha and IkappaBbeta and therefore activates NF-kappaBeta via at least two mechanisms: initially, through an IkappaB-independent mechanism, and later, via an increased turnover of the inhibitor IkappaB. NF-kappaBeta activation precedes the gene expression of iNOS (assayed by reverse transcription-polymerase chain reaction), suggesting that LPS up-regulates iNOS via this transcription factor.

We previously showed that group II phospholipase A2(PLA2-II), a secretory, bactericidal, and proinflammatory protein in intestinal crypts, is upregulated after lipopolysaccharide (LPS) and platelet-activating factor (PAF) challenge. Here we examined whether germ-free environment (GF) or antibiotic treatment (ABX) affects the pathophysiological responses and intestinal PLA2-II activity after PAF (1.5 μg/kg) or LPS (8 mg/kg) injection. We found that LPS and PAF induced hypotension and mild intestinal injury in conventionally fed (CN) rats; these changes were milder in ABX rats, whereas GF rats showed no intestinal injury. PLA2-II enzyme activity was detected in normal rat small intestine; the basal level was not diminished in ABX or GF rats. PAF and LPS caused an increase in PLA2-II activity, which was abrogated in GF and ABX rats. Recolonization of GF rats by enteral contamination restituted their PLA2-II response to PAF and LPS and susceptibility to bowel injury. We conclude that PAF- and LPS-induced increases in PLA2-II activity are dependent on gut bacteria, and ABX and GF rats are less susceptible to LPS-induced injury than CN rats.

Constitutive nitric oxide synthase (cNOS) may play an important protective role in the intestine, since our previous study has shown that the degree of bowel injury induced by platelet-activating factor (PAF), a potent inflammatory mediator, is inversely related to the cNOS content of the intestine. This study aims to examine the composition of the cNOS system in rat small intestine, and its regulation by PAF. We found that an approximately 120 kDa NOS I (neuronal NOS) is the predominant NOS in rat intestine, as evidenced by the following: (a) immunoblotting with specific antibodies detected a NOS I of approximately 120 kDa, but little NOS III; (b) the Ca 2+ -dependent, constitutive NOS (cNOS) activity of the rat intestine was removed by immunoprecipitation with the anti-NOS I, but not anti-NOS II or anti-NOS III antibodies; (c) RT–PCR revealed constitutive expression of NOS I in the intestinal tissue, but only a minute amount of NOS III. Immunofluorescent staining with anti-NOS I located NOS in the Auerbach plexus and nerve fibers in the muscle layer. We also found that this 120 kDa NOS I is rapidly (within 1 h) down-regulated in response to PAF administration. The protein level, enzyme activity as well as mRNA of nNOS were all decreased in the intestine.

Objective To examine the role of constitutive and inducible nitric oxide synthases (cNOS and iNOS) in platelet-activating factor (PAF)-induced shock and intestinal injury. Design Prospective, randomized, controlled experimental study. Setting Hospital research laboratory. Subjects Young adult male Sprague-Dawley rats were anesthetized and studied. Interventions Rats were injected with PAF, either alone or after the following pretreatments: a) selective iNOS inhibitors aminoguanidine or S-methylisothiourea; b) 3-morpholinosydnonimine, a NO donor; c) S-methylisothiourea + 3-morpholinosydnonimine; and d) antineutrophil antibody (to deplete neutrophils). Measurements and main results Blood pressure, hematocrit, white blood cell counts, intestinal injury, and intestinal cNOS and iNOS activities were assessed. We found that: a) cNOS is the predominant NOS in the intestine and its activity is inversely correlated to the level of tissue injury; b) there is a time-dependent increase in cNOS activity in sham-operated animals, which was abolished by PAF; c) Western blotting and immunohistochemistry showed iNOS present in the normal intestine, localizing mainly in crypt cells; d) iNOS inhibitors attenuated PAF-induced injury in animals with high cNOS activity, but had no protective effect in animals with low cNOS activity; e) 3-morpholinosydnonimine, alone or together with S-methylisothiourea, alleviated PAF-induced injury; and f) neutrophil depletion blocked the suppressive effect of PAF on cNOS and prevented injury. Conclusions We conclude that cNOS and iNOS play different roles in PAF-induced intestinal injury. Caution should be exerted concerning potential therapeutic uses of iNOS inhibitors.

Dysoxia can be defined as ATP flux decreasing in proportion to O2availability with preserved ATP demand. Hepatic venous β-hydroxybutyrate-to-acetoacetate ratio (β-OHB/AcAc) estimates liver mitochondrial NADH/NAD and may detect the onset of dysoxia. During partial dysoxia (as opposed to anoxia), however, flow may be adequate in some liver regions, diluting effluent from dysoxic regions, thereby rendering venous β-OHB/AcAc unreliable. To address this concern, we estimated tissue ATP while gradually reducing liver blood flow of swine to zero in a nuclear magnetic resonance spectrometer. ATP flux decreasing with O2availability was taken as O2uptake (V˙o2) decreasing in proportion to O2delivery (Q˙o2); and preserved ATP demand was taken as increasing Pi/ATP.V˙o2, tissue Pi/ATP, and venous β-OHB/AcAc were plotted againstQ˙o2to identify critical inflection points. Tissue dysoxia required meanQ˙o2for the group to be critical for bothV˙o2and for Pi/ATP. CriticalQ˙o2values forV˙o2and Pi/ATP of 4.07 ± 1.07 and 2.39 ± 1.18 (SE) ml ⋅ 100 g−1⋅ min−1, respectively, were not statistically significantly different but not clearly the same, suggesting the possibility that dysoxia might have commenced after V˙o2began decreasing, i.e., that there could have been “O2conformity.” CriticalQ˙o2for venous β-OHB/AcAc was 2.44 ± 0.46 ml ⋅ 100 g−1⋅ min−1( P = NS), nearly the same as that for Pi/ATP, supporting venous β-OHB/AcAc as a detector of dysoxia. All issues considered, tissue mitochondrial redox state seems to be an appropriate detector of dysoxia in liver.

In a previous study, we showed that anti-CD11b or anti-CD18 antibody markedly attenuated platelet-activating factor (PAF)-induced shock and intestinal necrosis in rats, whereas anti-P-selectin anti-body was ineffective. Here we used genetically altered mice to study the mechanism of PAF in mice. We found that P-selectin-deficient mice are completely protected from the adverse effects of PAF with no mortality or intestinal injury and only mild hemoconcentration and transient hypotension. In contrast, CD18- or intercellular adhesion molecule 1 (ICAM-1)-deficient mice were not protected from PAF-induced tissue injury and death. However, when ICAM-1-, but not CD18-, deficient mice were pretreated with fucoidin, the adverse effects of PAF were markedly reduced; survival was 100%, although hypotension still developed. Neutrophil-depleted mice were protected from PAF-induced intestinal injury but still developed hypotension and hemoconcentration. PAF increases peripheral blood neutrophil counts, probably by inducing granulopoiesis, since neutrophil-depleted mice still showed granulocytosis 60 min after PAF. Thus P-selectin plays an important role in PAF-induced injury in mice, and the selectins and the integrin-ICAM-1 system work in concert to mediate the inflammatory response to PAF in vivo.

Rozenfeld, Ranna A., Michael K. Dishart, Tor Inge Tønnessen, and Robert Schlichtig. Methods for detecting local intestinal ischemic anaerobic metabolic acidosis by[Formula: see text]. J. Appl. Physiol. 81(4): 1834–1842, 1996.—Gut ischemia is often assessed by computing an imaginary tissue interstitial pH from arterial plasma [Formula: see text] and the[Formula: see text] in a saline-filled balloon tonometer after equilibration with tissue[Formula: see text](P[Formula: see text]). P[Formula: see text] may alternatively be assumed equal to venous[Formula: see text]([Formula: see text]) in that region of gut. The idea is that as blood flow decreases, gut P[Formula: see text] and[Formula: see text] will increase to the maximum aerobic value, i.e., maximum respiratory[Formula: see text]([Formula: see text]). Above a “critical” anaerobic threshold, lactate (La−) generation, by titration of tissue [Formula: see text], should raise P[Formula: see text]above[Formula: see text]. During progressive selective whole intestinal flow reduction in six pentobarbital-anesthetized pigs, we used[Formula: see text] electrodes to test the hypotheses that critical P[Formula: see text]is achieved earlier in mucosa than in serosa and that[Formula: see text], computed using an in vitro model, predicts critical P[Formula: see text]. We defined critical P[Formula: see text] as the inflection of P[Formula: see text]-[Formula: see text]vs. O2delivery (Q˙o2) plots. CriticalQ˙o2for O2uptake was 12.55 ± 2 ml ⋅ kg−1⋅ min−1. Critical P[Formula: see text] for mucosa and serosa was achieved at similar whole intestineQ˙o2(13.90 ± 5 and 13.36 ± 5 ml ⋅ kg−1⋅ min−1, P = NS). Critical P[Formula: see text] (129 ± 24 and 96 ± 21 Torr) exceeded[Formula: see text](62 ± 3 Torr). During ischemia, La−excretion into portal venous blood was matched by K+excretion, causing [Formula: see text] to increase only slightly, despite P[Formula: see text] rising to 380 ± 46 (mucosa) and 280 ± 38 (serosa) Torr. These results suggest that mucosa and serosa become dysoxic simultaneously, that ischemic dysoxic gut is essentially unperfused, and that in vitro predicted[Formula: see text]underestimates critical P[Formula: see text].

Severe sepsis is associated with dysfunction of the macrophage/monocyte, an important cellular effector of the innate immune system. Previous investigations suggested that probiotic components effectively enhance effector cell functions of the immune system in vivo. In this study, we produced bacteria-free, lysozyme-modified probiotic components (LzMPC) by treating the probiotic bacteria, Lactobacillus sp., with lysozyme. We showed that oral delivery of LzMPC effectively protected rats against lethality from polymicrobial sepsis induced by cecal ligation and puncture. We found that orally administrated LzMPC was engulfed by cells such as macrophages in the liver after crossing the intestinal barrier. Moreover, LzMPC-induced protection was associated with an increase in bacterial clearance in the liver. In vitro, LzMPC up-regulated the expression of cathelicidin-related antimicrobial peptide (CRAMP) in macrophages and enhanced bactericidal activity of these cells. Furthermore, we demonstrated that surgical stress or cecal ligation and puncture caused a decrease in CRAMP expression in the liver, whereas enteral administration of LzMPC restored CRAMP gene expression in these animals. Using a neutralizing Ab, we showed that protection against sepsis by LzMPC treatment required endogenous CRAMP. In addition, macrophages from LzMPC-treated rats had an enhanced capacity of cytokine production in response to LPS or LzMPC stimulation. Together, our data suggest that the protective effect of LzMPC in sepsis is related to an enhanced cathelicidin-related innate immunity in macrophages. Therefore, LzMPC, a novel probiotic product, is a potent immunomodulator for macrophages and may be beneficial for the treatment of sepsis.

We reported previously that neuronal nitric oxide synthase (nNOS) is the predominant NOS in rat small intestine and is down-regulated by platelet-activating factor (PAF). The severity of the bowel injury induced by PAF is inversely related to its suppressing effect on nNOS. Here, we investigated whether intestinal perfusion is regulated by nNOS and whether tetrahydrobiopterin, a co-factor and stabilizer of nNOS, reverses PAF-induced intestinal hypoperfusion and injury.Animal laboratory.We first examined nNOS regulation of splanchnic blood flow by measuring the perfusion of the heart, lung, ileum, and kidney in rats after a nNOS inhibitor. We then examined the protective effect of tetrahydrobiopterin on PAF-induced bowel injury, mesenteric hypoperfusion, and systemic inflammation.Adult male Sprague-Dawley rats.In part 1 of the experiment, rats were given 7-nitroindazole (a specific nNOS inhibitor, 50 mg.kg.day). In part 2 of the experiment, rats were treated with tetrahydrobiopterin (20 mg/kg) 5 mins before and 30 mins after PAF challenge (2.2 microg/kg, intravenously)Perfusion of the heart, lung, ileum, and kidney was measured at 1 and 4 days after 7-nitroindazole, using fluorescent microspheres. Intestinal injury and inflammation (myeloperoxidase content), blood perfusion, calcium dependent-NOS activity, and systemic inflammation (hypotension and hematocrit increase) were assessed 1 hr after PAF with and without tetrahydrobiopterin treatment.In part 1 of the experiment, 7-nitroindazole induced a long-lasting reduction of blood perfusion and inducible NOS expression selectively in the ileum but not in nonsplanchnic organs such as heart, lungs, and kidneys. In part 2, tetrahydrobiopterin protected against PAF-induced intestinal necrosis, hypoperfusion, neutrophil influx, and NOS suppression. It also reversed hypotension and hemoconcentration. Sepiapterin (2 mg/kg, stable tetrahydrobiopterin precursor) also attenuated PAF-induced intestinal injury.We conclude that nNOS selectively regulates intestinal perfusion. Tetrahydrobiopterin prevents PAF-induced intestinal injury, probably by stabilizing nNOS and maintaining intestinal perfusion.

We previously reported that neuronal nitric oxide synthase (nNOS) is the predominant NOS in the intestine. Inducible NOS (iNOS), an enzyme involved in the inflammatory response, is regulated by cytokines via the transcriptional factor NF-kappaB. We examined a new mechanism of intestinal iNOS regulation with respect to the role of nNOS and its effect on NF-kappaB. Young Sprague-Dawley rats were treated for 4 days with 1) saline, 2) 7-nitroindazole (7-NI, specific nNOS inhibitor), 3) 7-NI + pyrrolidine dithiocarbamate (PDTC, NF-kappaB inhibitor), or 4) PDTC. Intestinal iNOS mRNA, NF-kappaB activity, and the tissue content of the regulatory IkappaBalpha were examined. We found that 7-NI-treated animals had higher intestinal NF-kappaB (p50-p65) activity, lower IkappaBalpha content, and increased intestinal iNOS mRNA, iNOS protein, and iNOS activity compared with controls. All of these changes were abolished when PDTC was given together with 7-NI. PDTC alone had no effect. 7-NI induces a delayed increase in intestinal myeloperoxidase activity (after elevation in NF-kappaB and iNOS), which could be abrogated by PDTC. We conclude that in normal rat small intestine, nNOS suppresses the gene expression of iNOS through NF-kappaB down-regulation and that nNOS suppression leads to IkappaBalpha degradation, NF-kappaB activation, and iNOS expression.

BackgroundXanthine oxidase (XO) is an important source of reactive oxygen species in the small intestine.AimsTo examine the interaction of platelet activating factor (PAF), XO, and neutrophils in mediating intestinal injury in rats.MethodsTwo doses of PAF were used to induce either reversible hypotension, or irreversible shock with intestinal necrosis. The activities of XO, and its precursor xanthine dehydrogenase (XD), in both the whole intestinal tissue and epithelial cells, were measured. XO was localised by histochemical staining.ResultsPAF dose dependently induced an increase in XO activity, predominantly in the ileal epithelium, without altering the total activity of XD+XO. Most of the XD to XO conversion was via proteolysis. PAF induced XO activation and intestinal injury were prevented by prior neutrophil depletion. PAF induced XO activation is probably not due to reperfusion, as XO activation preceded the recovery of mesenteric flow. Allopurinol pretreatment substantially inhibited intestinal neutrophil sequestration induced by high dose (but not low dose) PAF.ConclusionsPAF rapidly activates intestinal XO through proteolytic XD-XO conversion, predominantly in the ileal epithelium. This effect is mediated by neutrophils. XO activation promotes PAF induced polymorphonuclear leucocyte sequestration in the intestine.

PAF (platelet-activating factor, Paf-acether, 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine), a phospholipid with potent biological effects (Benveniste, 1988; Snyder, 1990), is one of the main mediators in endotoxin shock, as supported by the following observations: (a) serum PAF level rises in sepsis (Heuer et al. 1991); (b) plasma PAF increases in animals following injection of lipopolysaccharide (LPS) (Chang et al. 1987; Dobrowsky et al. 1991), and the tissue PAF content is elevated in LPS-induced injury of the lung (Chang et al. 1987) and bowel (Hsueh et al. 1987); (c) PAF injection causes shock and tissue injury, mimicking the effect of LPS in vivo (Benveniste, 1988; Handley, 1990); and (d) furthermore, pretreatment with PAF antagonists prevents LPS-induced shock (Handley, 1990; Dobrowsky et al. 1991). Since PAF is generally considered to be an autacoid, or local hormone, the content of PAF in the inflamed or injured tissues appears to be a more meaningful indicator than its serum level. However, tissue PAF production in inflammation has been studied to a limited extent, perhaps partly due to technical difficulties. Our previous animal studies have shown that the small intestine is the target of LPS-induced injury, and a high PAF level in the intestinal mucosa has been demonstrated following LPS administration (Hsueh et al. 1987). However, there has been no study comparing the endogenous PAF production of various organs. In endotoxin shock plasma volume is reduced and haemoconcentration develops. Although the mechanism is unclear, it is generally assumed that blood volume changes are a consequence of the release of mediators such as tumour necrosis factor-α (TNF), PAF and peptide leukotrienes, with resulting vascular leakage or peripheral vasodilatation and venous blood pooling. An important physiological regulator of plasma volume is atrial natriuretic peptide (ANP), a cardiac hormone with profound effects on the cardiovascular system and kidneys (Espiner, 1994). Despite its potent vascular regulatory effect, and known changes in endotoxin shock (Gullichsen et al. 1989), its role in the pathophysiology of septic shock has not been studied. The goals of the present study are: (a) to compare the PAF level in various visceral organs in response to LPS; (b) to ascertain the possible cellular source of PAF in these organs; (c) to define the role of the spleen and PAF in the regulation of blood volume in endotoxin shock; and (d) to study the interaction of PAF, spleen and ANP in endotoxin shock. We report here that splenic tissue is the site of the highest PAF biosynthesis during endotoxaemia, and that endogenous PAF induces ANP production, which may mediate plasma volume reduction.

The Role of Intestinal Flora in Endotoxin (LPS)-Induced Gut Injury and Group II Phospholipase A 2 (PLA 2 -II) Activation in the Small Intestine

The Effects of Nitric Oxide Synthase (NOS) Inhibitors and Nitric Oxide (NO) Donors on Endotoxin (LPS)-Induced Shock and Intestinal Injury • 229

Background Assessing the ventilatory status of non-intubated infants in the Pediatric Intensive Care Unit (PICU) is a constant challenge. Methods to evaluate ventilation include arterial blood gas analysis (ABG), which is invasive and intermittent, and transcutaneous carbon dioxide monitoring (PtcCO2), which, while non-invasive, is also intermittent. A method that is non-invasive and continuous would be of great benefit in this population. We hypothesized that non-invasive capnometry via sidestream monitoring of exhaled carbon dioxide (CO2) would provide an acceptable measurement of ventilatory status when compared to ABG or PtcCO2. Methods Preliminary prospective study of infants less than one year of age admitted to the PICU in a large urban teaching hospital. Infants not intubated and not requiring non-invasive ventilation were eligible. A sidestream CO2 reading was obtained in a convenience sample of 39 patients. A simultaneous ABG was collected in those with an arterial catheter, and a PtcCO2 was obtained in those without. Results Correlation of sidestream CO2 with ABG was excellent (r2 = 0.907). Sidestream correlated less well with PtcCO2 (r2 = 0.649). Results were not significantly altered when weight and respiratory rate were added as independent variables. Bland-Altman analysis revealed a bias of -2.7 with a precision of ±6.5 when comparing sidestream CO2 to ABG, and a bias of -1.7 with a precision of ±9.9 when comparing sidestream CO2 to PtcCO2. Conclusions Performance of sidestream monitoring of exhaled CO2 is acceptable clinical trending to assess the effectiveness of ventilation in non-intubated infants in the PICU.

Background The transport of critically ill patients to children’s hospitals is essential to current practice. The AAP Section on Transport Medicine has raised concerns about future leadership in the field as trainees receive less exposure to transport medicine. This study identifies the priorities of pediatric subspecialty fellows, fellowship directors and nursing directors in transport medicine education. Methods Internet based surveys were distributed to fellows, fellowship directors and nursing directors of transport teams affiliated with ACGME-approved fellowships in Neonatal-Perinatal Medicine (NPM), Pediatric Critical Care Medicine (PCCM), and Pediatric Emergency Medicine (PEM). Data collection occurred November 2013 to March 2014. Results Four hundred and sixty-six responses were collected (357 fellows, 82 directors, 27 nursing directors): Six curricular elements were ranked by respondents: Transport Physiology (TP), Medical Control (MC), Vehicle Safety (VS), Medicolegal Issues (ML), Medical Protocols (MP) and State and Federal Regulations (SFR). Fellows and fellowship directors were not significantly different: TP (p = 0.63), VS (p = 0.45), SFR (p = 0.58), ML (p = 0.07), MP (p = 0.98), and MC (p = 0.36). Comparison of subspecialties found significant differences: PEM considered TP less important than NPM and PCCM (p