Risk factors for ventilator-associated lower respiratory tract infection in COVID-19, a retrospective multicenter cohort study in Sweden.

BACKGROUND: Ventilator-associated lower respiratory tract infections (VA-LRTI) increase morbidity and mortality in intensive care unit (ICU) patients. Higher incidences of VA-LRTI have been reported among COVID-19 patients requiring invasive mechanical ventilation (IMV). The primary objectives of this study were to describe clinical characteristics, incidence, and risk factors comparing patients who developed VA-LRTI to patients who did not, in a cohort of Swedish ICU patients with acute hypoxemic respiratory failure due to COVID-19. Secondary objectives were to decipher changes over the three initial pandemic waves, common microbiology and the effect of VA-LTRI on morbidity and mortality. METHODS: We conducted a multicenter, retrospective cohort study of all patients admitted to 10 ICUs in southeast Sweden between March 1, 2020 and May 31, 2021 because of acute hypoxemic respiratory failure due to COVID-19 and were mechanically ventilated for at least 48 h. The primary outcome was culture verified VA-LRTI. Patient characteristics, ICU management, clinical course, treatments, microbiological findings, and mortality were registered. Logistic regression analysis was conducted to determine risk factors for first VA-LRTI. RESULTS: Of a total of 536 included patients, 153 (28.5%) developed VA-LRTI. Incidence rate of first VA-LRTI was 20.8 per 1000 days of IMV. Comparing patients with VA-LRTI to those without, no differences in mortality, age, sex, or number of comorbidities were found. Patients with VA-LRTI had fewer ventilator-free days, longer ICU stay, were more frequently ventilated in prone position, received corticosteroids more often and were more frequently on antibiotics at intubation. Regression analysis revealed increased adjusted odds-ratio (aOR) for first VA-LRTI in patients treated with corticosteroids (aOR 2.64 [95% confidence interval [CI]] [1.31-5.74]), antibiotics at intubation (aOR 2.01 95% CI [1.14-3.66]), and days of IMV (aOR 1.05 per day of IMV, 95% CI [1.03-1.07]). Few multidrug-resistant pathogens were identified. Incidence of VA-LRTI increased from 14.5 per 1000 days of IMV during the first wave to 24.8 per 1000 days of IMV during the subsequent waves. CONCLUSION: We report a high incidence of culture-verified VA-LRTI in a cohort of critically ill COVID-19 patients from the first three pandemic waves. VA-LRTI was associated with increased morbidity but not 30-, 60-, or 90-day mortality. Corticosteroid treatment, antibiotics at intubation and time on IMV were associated with increased aOR of first VA-LRTI.

Identification of myocardial injury using perioperative troponin surveillance in major noncardiac surgery and net benefit over the Revised Cardiac Risk Index.

BACKGROUND: Patients with perioperative myocardial injury are at risk of death and major adverse cardiovascular and cerebrovascular events (MACCE). The primary aim of this study was to determine optimal thresholds of preoperative and perioperative changes in high-sensitivity cardiac troponin T (hs-cTnT) to predict MACCE and mortality. METHODS: Prospective, observational, cohort study in patients ≥50 yr of age undergoing elective major noncardiac surgery at seven hospitals in Sweden. The exposures were hs-cTnT measured before and days 0-3 after surgery. Two previously published thresholds for myocardial injury and two thresholds identified using receiver operating characteristic analyses were evaluated using multivariable logistic regression models and externally validated. The weighted comparison net benefit method was applied to determine the additional value of hs-cTnT thresholds when compared with the Revised Cardiac Risk Index (RCRI). The primary outcome was a composite of 30-day all-cause mortality and MACCE. RESULTS: We included 1291 patients between April 2017 and December 2020. The primary outcome occurred in 124 patients (9.6%). Perioperative increase in hs-cTnT ≥14 ng L-1 above preoperative values provided statistically optimal model performance and was associated with the highest risk for the primary outcome (adjusted odds ratio 2.9, 95% confidence interval 1.8-4.7). Validation in an independent, external cohort confirmed these findings. A net benefit over RCRI was demonstrated across a range of clinical thresholds. CONCLUSIONS: Perioperative increases in hsTnT ≥14 ng L-1 above baseline values identifies acute perioperative myocardial injury and provides a net prognostic benefit when added to RCRI for the identification of patients at high risk of death and MACCE. CLINICAL TRIAL REGISTRATION: NCT03436238.

Introduction of a rapid sequence induction checklist and its effect on compliance to guidelines and complications.

BACKGROUND: Current evidence for the conduct of rapid sequence induction (RSI) is weak. This increases the risk of clinicians modifying the RSI procedure according to personal preferences. Checklists may help increase compliance to best practice guidelines and reduce complication rates. Their value during RSI, a critical procedure in anaesthesia, is unknown. The aim of this study was to investigate compliance to local guidelines and frequency of RSI-related complications before and after introduction of an RSI checklist. METHODS: This was a prospective, observational, pre- and post-intervention study conducted at two hospitals. There were two interventions: the first was a standardized educational lecture to all staff at both hospitals, consisting of an educational instruction of the checklist and general information about RSI, and the second intervention was the introduction of a RSI checklist. The checklist consisted of 16 items. Compliance to guidelines was categorized as high, moderate and low, and was assessed pre- and post-intervention. The frequency of RSI-related complications was also measured. RESULTS: We registered 811 RSI procedures of which 412 were pre-intervention. After intervention, the proportion of procedures with high compliance to RSI guidelines increased from 49% to 70% (P < .001). The proportion with partial and low compliance decreased from 37% to 26% (P < .001) and 13% to 3.3% (P < .001) respectively. No change in RSI-related complication rates was detectable post-intervention (16.6%-16.7% P = .56). CONCLUSION: The introduction of a structured RSI checklist significantly increased compliance to RSI guidelines. A change in RSI-related complications could not be detected due to the size of the study. A checklist may be a useful tool to reduce variance during the RSI procedure.

The involvement of prostaglandin E2 in interleukin-1ß evoked anorexia is strain dependent.

From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1-4) that was critical for the anorexic response to peripherally injected interleukin-1ß (IL-1ß). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1ß induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1ß evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1ß in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1ß; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1ß evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

Characterization of brown adipose tissue by water-fat separated magnetic resonance imaging.

BACKGROUND: To evaluate the possibility of quantifying brown adipose tissue (BAT) volume and fat concentration with a high resolution, long echo time, dual-echo Dixon imaging protocol. METHODS: A 0.42 mm isotropic resolution water-fat separated MRI protocol was implemented by using the second opposite-phase echo and third in-phase echo. Fat images were calibrated with regard to the intensity of nearby white adipose tissue (WAT) to form relative fat content (RFC) images. To evaluate the ability to measure BAT volume and RFC contrast dynamics, rats were divided into two groups that were kept at 4° or 22°C for 5 days. The rats were then scanned in a 70 cm bore 3.0 Tesla MRI scanner and a human dual energy CT. Interscapular, paraaortal, and perirenal BAT (i/pa/pr-BAT) depots as well as WAT and muscle were segmented in the MRI and CT images. Biopsies were collected from the identified BAT depots. RESULTS: The biopsies confirmed that the three depots identified with the RFC images consisted of BAT. There was a significant linear correlation (P < 0.001) between the measured RFC and the Hounsfield units from DECT. Significantly lower iBAT RFC (P = 0.0064) and significantly larger iBAT and prBAT volumes (P = 0.0017) were observed in the cold stimulated rats. CONCLUSION: The calibrated Dixon images with RFC scaling can depict BAT and be used to measure differences in volume, and fat concentration, induced by cold stimulation. The high correlation between RFC and HU suggests that the fat concentration is the main RFC image contrast mechanism.

ACETAMINOPHEN ATTENUATES PULMONARY VASCULAR RESISTANCE AND PULMONARY ARTERIAL PRESSURE AND INHIBITS CARDIOVASCULAR COLLAPSE IN A PORCINE MODEL OF ENDOTOXEMIA.

ABSTRACT: Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 µg/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-α in blood. As a proof of concept, we injected a high dose of endotoxin (100 µg), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.

Inducible prostaglandin E2 synthesis interacts in a temporally supplementary sequence with constitutive prostaglandin-synthesizing enzymes in creating the hypothalamic-pituitary-adrenal axis response to immune challenge.

Inflammation-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis has been suggested to depend on prostaglandins, but the prostaglandin species and the prostaglandin-synthesizing enzymes that are responsible have not been fully identified. Here, we examined HPA axis activation in mice after genetic deletion or pharmacological inhibition of prostaglandin E(2)-synthesizing enzymes, including cyclooxygenase-1 (Cox-1), Cox-2, and microsomal prostaglandin E synthase-1 (mPGES-1). After immune challenge by intraperitoneal injection of lipopolysaccharide, the rapid stress hormone responses were intact after Cox-2 inhibition and unaffected by mPGES-1 deletion, whereas unselective Cox inhibition blunted these responses, implying the involvement of Cox-1. However, mPGES-1-deficient mice showed attenuated transcriptional activation of corticotropin-releasing hormone (CRH) that was followed by attenuated plasma concentrations of adrenocorticotropic hormone and corticosterone. Cox-2 inhibition similarly blunted the delayed corticosterone response and further attenuated corticosterone release in mPGES-1 knock-out mice. The expression of the c-fos gene, an index of synaptic activation, was maintained in the paraventricular hypothalamic nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. These findings point to a mechanism by which (1) neuronal afferent signaling via brainstem autonomic relay nuclei and downstream Cox-1-dependent prostaglandin release and (2) humoral, CRH transcription-dependent signaling through induced Cox-2 and mPGES-1 elicited PGE(2) synthesis, shown to occur in brain vascular cells, play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

Acetaminophen reduces lipopolysaccharide-induced fever by inhibiting cyclooxygenase-2.

Acetaminophen is one of the world's most commonly used drugs to treat fever and pain, yet its mechanism of action has remained unclear. Here we tested the hypothesis that acetaminophen blocks fever through inhibition of cyclooxygenase-2 (Cox-2), by monitoring lipopolysaccharide induced fever in mice with genetic manipulations of enzymes in the prostaglandin cascade. We exploited the fact that lowered levels of a specific enzyme make the system more sensitive to any further inhibition of the same enzyme. Mice were immune challenged by an intraperitoneal injection of bacterial wall lipopolysaccharide and their body temperature recorded by telemetry. We found that mice heterozygous for Cox-2, but not for microsomal prostaglandin E synthase-1 (mPGES-1), displayed attenuated fever, indicating a rate limiting role of Cox-2. We then titrated a dose of acetaminophen that did not inhibit the lipopolysaccharide-induced fever in wild-type mice. However, when the same dose of acetaminophen was given to Cox-2 heterozygous mice, the febrile response to lipopolysaccharide was strongly attenuated, resulting in an almost normalized temperature curve, whereas no difference was seen between wild-type and heterozygous mPGES-1 mice. Furthermore, the fever to intracerebrally injected prostaglandin E2 was unaffected by acetaminophen treatment. These findings reveal that acetaminophen, similar to aspirin and other non-steroidal anti-inflammatory drugs, is antipyretic by inhibiting cyclooxygenase-2, and not by inhibiting mPGES-1 or signaling cascades downstream of prostaglandin E2.

Evidence for two types of brown adipose tissue in humans.

The previously observed supraclavicular depot of brown adipose tissue (BAT) in adult humans was commonly believed to be the equivalent of the interscapular thermogenic organ of small mammals. This view was recently disputed on the basis of the demonstration that this depot consists of beige (also called brite) brown adipocytes, a newly identified type of brown adipocyte that is distinct from the classical brown adipocytes that make up the interscapular thermogenic organs of other mammals. A combination of high-resolution imaging techniques and histological and biochemical analyses showed evidence for an anatomically distinguishable interscapular BAT (iBAT) depot in human infants that consists of classical brown adipocytes, a cell type that has so far not been shown to exist in humans. On the basis of these findings, we conclude that infants, similarly to rodents, have the bona fide iBAT thermogenic organ consisting of classical brown adipocytes that is essential for the survival of small mammals in a cold environment.

Cyclooxygenase-1 mediates the immediate corticosterone response to peripheral immune challenge induced by lipopolysaccharide.

Immune-induced activation of the hypothalamus-pituitary-adrenal axis is mediated by cyclooxygenase derived prostaglandins. Here we examined the role of cyclooxygenase-1 in this response, by using genetically modified mice as well as pharmacological inhibition. We found that mice with a deletion of the gene encoding cyclooxygenase-1, in contrast to wild type mice, did not show increased plasma corticosterone at 1h after immune challenge by peripheral injection of bacterial wall lipopolysaccharide, whereas the corticosterone levels were similarly elevated in both genotypes at 6h post-injection. Pretreatment of mice with the selective cyclooxygenase-1 inhibitor SC-560, given orally, likewise inhibited the rapid corticosterone response. These findings, taken together with our recent demonstration that the delayed stress hormone response to immune challenge is dependent on cyclooxygenase-2, show that the two cyclooxygenase isoforms play distinct, but temporally supplementary roles for the stress hormone response to inflammation.

The role of interleukin-6 in lipopolysaccharide-induced fever by mechanisms independent of prostaglandin E2.

Fever has been shown to be elicited by prostaglandin E(2) (PGE(2)) binding to its receptors on thermoregulatory neurons in the anterior hypothalamus. The signals that trigger PGE(2) production are thought to include proinflammatory cytokines, such as IL-6. However, although the presence of IL-6 is critical for fever, IL-6 by itself is not or only weakly pyrogenic. Here we examined the relationship between IL-6 and PGE(2) in lipopolysaccharide (LPS)-induced fever. Immune-challenged IL-6 knockout mice did not produce fever, in contrast to wild-type mice, but the expression of the inducible PGE(2)-synthesizing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase-1, was similarly up-regulated in the hypothalamus of both genotypes, which also displayed similarly elevated PGE(2) levels in the cerebrospinal fluid. Nevertheless, both wild-type and knockout mice displayed a febrile response to graded concentrations of PGE(2) injected into the lateral ventricle. There was no major genotype difference in the expression of IL-1beta and TNFalpha or their receptors, and pretreatment of IL-6 knockout mice with soluble TNFalpha receptor ip or intracerebroventricularly or a cyclooxygenase-2 inhibitor ip did not abolish the LPS unresponsiveness. Hence, although IL-6 knockout mice have both an intact PGE(2) synthesis and an intact fever-generating pathway downstream of PGE(2), endogenously produced PGE(2) is not sufficient to produce fever in the absence of IL-6. The findings suggest that IL-6 controls some factor(s) in the inflammatory cascade, which render(s) IL-6 knockout mice refractory to the pyrogenic action of PGE(2), or that it is involved in the mechanisms that govern release of synthesized PGE(2) onto its target neurons.

IL-1beta and LPS induce anorexia by distinct mechanisms differentially dependent on microsomal prostaglandin E synthase-1.

Recent work demonstrated that the febrile response to peripheral immune stimulation with proinflammatory cytokine IL-1beta or bacterial wall lipopolysaccharide (LPS) is mediated by induced synthesis of prostaglandin E(2) by the terminal enzyme microsomal prostaglandin E synthase-1 (mPGES-1). The present study examined whether a similar mechanism might also mediate the anorexia induced by these inflammatory agents. Transgenic mice with a deletion of the Ptges gene, which encodes mPGES-1, and wild-type controls were injected intraperitoneally with IL-1beta, LPS, or saline. Mice were free fed, and food intake was continuously monitored with an automated system for 12 h. Body weight was recorded every 24 h for 4 days. The IL-1beta induced anorexia in wild-type but not knock-out mice, and so it was almost completely dependent on mPGES-1. In contrast, LPS induced anorexia of the same magnitude in both phenotypes, and hence it was independent of mPGES-1. However, when the mice were prestarved for 22 h, LPS induced anorexia and concomitant body weight loss in the knock-out animals that was attenuated compared with the wild-type controls. These data suggest that IL-1beta and LPS induce anorexia by distinct immune-to-brain signaling pathways and that the anorexia induced by LPS is mediated by a mechanism different from the fever induced by LPS. However, nutritional state and/or motivational factors also seem to influence the pathways for immune signaling to the brain. Furthermore, both IL-1beta and LPS caused reduced meal size but not meal frequency, suggesting that both agents exerted an anhedonic effect during these experimental conditions.