Nicholas Heming

Anti-inflammatory role of the IgA Fc receptor (CD89): from autoimmunity to therapeutic perspectives.

The human immunoglobulin A (IgA) plays a key role in immune protection. IgA is the second most prevalent antibody in the serum. IgA-deficient patients frequently develop autoimmune or inflammatory diseases. The IgA function is mainly mediated through its interaction with the myeloid IgA Fc receptor FcαRI (CD89). FcαRI, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor, has a dual function in immunity. Monovalent targeting of FcαRI, by anti-FcαRI Fab or monomeric IgA, triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain. This results in a low-intensity signaling cascade promoting recruitment of the tyrosine phosphatase SHP-1, which induces cell inhibition of multiple types of activation signals. In contrast, cross-linking of FcαRI by multimeric ligand induces a high-intensity signaling pathway that leads to the recruitment of the tyrosine kinase Syk and to cell activation. Thus, FcαRI acts as a regulator, which mediates both anti- and pro-inflammatory functions of IgA depending on the type of interaction. This balance is of great importance to prevent tissue damage in immunopathology and to ensure the return of activated cells to a resting state. The role of the IgA-FcαRI interaction in the activation of different signaling pathways and its multifaceted role in immunity are discussed.

Clinical review: Intrapericardial fibrinolysis in management of purulent pericarditis

Purulent pericarditis (PP) is a potentially life-threatening disease. Reported mortality rates are between 20 and 30%. Constrictive pericarditis occurs over the course of PP in at least 3.5% of cases. The frequency of persistent PP (chronic or recurrent purulent pericardial effusion occurring despite drainage and adequate antibiotherapy) is unknown because this entity was not previously classified as a complication of PP. No consensus exists on the optimal management of PP. Nevertheless, the cornerstone of PP management is complete eradication of the focus of infection. In retrospective studies, compared to simple drainage, systematic pericardiectomy provided a prevention of constrictive pericarditis with better clinical outcome. Because of potential morbidity associated with pericardiectomy, intrapericardial fibrinolysis has been proposed as a less invasive method for prevention of persistent PP and constrictive pericarditis. Experimental data demonstrate that fibrin formation, which occurs during the first week of the disease, is an essential step in the evolution to constrictive pericarditis and persistent PP. We reviewed the literature using the MEDLINE database. We evaluated the clinical efficacy, outcome, and complications of pericardial fibrinolysis. Seventy-four cases of fibrinolysis in PP were analysed. Pericarditis of tuberculous origin were excluded. Among the 40 included cases, only two treated by late fibrinolysis encountered failure requiring pericardiectomy. No patient encountered clinical or echocardiographic features of constriction during follow-up. Only one serious complication was described. Despite the lack of definitive evidence, potential benefits of fibrinolysis as a less invasive alternative to surgery in the management of PP seem promising. Early consideration should be given to fibrinolysis in order to prevent both constrictive and persistent PP. Nevertheless, in case of failure of fibrinolysis, pericardiectomy remains the primary option for complete eradication of infection.

Efficacy and toxicity of intravenous iron in a mouse model of critical care anemia

Objective:Anemia is common in critically ill patients, due to inflammation and blood loss. Anemia can be associated with iron deficiency and low serum hepcidin levels. However, iron administration in this setting remains controversial because of its potential toxicity, including oxidative stress induction and sepsis facilitation. The objective of this work was to determine the efficacy and toxicity of iron administration using a mouse model mimicking critical care anemia as well as a model of acute septicemia. Design:Prospective, randomized, open label controlled animal study. Setting:University-based research laboratory. Subjects:C57BL/6 and OF1 mice. Interventions:Intraperitoneal injection of zymosan inducing generalized inflammation in C57BL/6 mice, followed in our full model by repeated phlebotomies. A dose equivalent to 15 mg/kg of ferric carboxymaltose was injected intravenously on day 5. To assess the toxicity of iron in a septicemia model, OF1 mice were simultaneously injected with iron and different Escherichia coli strains. Measurements and Main Results:To investigate the effect of iron on oxidative stress, we measured reactive oxygen species production in the blood using luminol-amplified chemiluminescence and superoxide dismutase 2 messenger RNA levels in the liver. These markers of oxidative stress were increased after iron administration in control mice but not in zymosan-treated mice. Liver catalase messenger RNA levels decreased in iron-treated control mice. Iron administration was not associated with increased mortality in the septicemia model or in the generalized inflammation model. Iron increased hemoglobin levels in mice fed with a low iron diet and subjected to phlebotomies and zymosan 2 wks after treatment administration. Conclusions:Adverse effects of intravenous iron supplementation by ferric carboxymaltose seem to be minimal in our animal models. Furthermore, iron appears to be effective in correcting anemia, despite inflammation. Studies of efficacy and safety of iron in critically ill patients are warranted.

Early Standard Electroencephalogram Abnormalities Predict Mortality in Septic Intensive Care Unit Patients.

Introduction Sepsis is associated with increased mortality, delirium and long-term cognitive impairment in intensive care unit (ICU) patients. Electroencephalogram (EEG) abnormalities occurring at the acute stage of sepsis may correlate with severity of brain dysfunction. Predictive value of early standard EEG abnormalities for mortality in ICU septic patients remains to be assessed. Methods In this prospective, single center, observational study, standard EEG was performed, analyzed and classified according to both Synek and Young EEG scales, in consecutive patients acutely admitted in ICU for sepsis. Delirium, coma and the level of sedation were assessed at the time of EEG recording; and duration of sedation, occurrence of in-ICU delirium or death were assessed during follow-up. Adjusted analyses were carried out using multiple logistic regression. Results One hundred ten patients were included, mean age 63.8 (±18.1) years, median SAPS-II score 38 (29–55). At the time of EEG recording, 46 patients (42%) were sedated and 22 (20%) suffered from delirium. Overall, 54 patients (49%) developed delirium, of which 32 (29%) in the days after EEG recording. 23 (21%) patients died in the ICU. Absence of EEG reactivity was observed in 27 patients (25%), periodic discharges (PDs) in 21 (19%) and electrographic seizures (ESZ) in 17 (15%). ICU mortality was independently associated with a delta-predominant background (OR: 3.36; 95% CI [1.08 to 10.4]), absence of EEG reactivity (OR: 4.44; 95% CI [1.37–14.3], PDs (OR: 3.24; 95% CI [1.03 to 10.2]), Synek grade ≥ 3 (OR: 5.35; 95% CI [1.66–17.2]) and Young grade > 1 (OR: 3.44; 95% CI [1.09–10.8]) after adjustment to Simplified Acute Physiology Score (SAPS-II) at admission and level of sedation. Delirium at the time of EEG was associated with ESZ in non-sedated patients (32% vs 10%, p = 0.037); with Synek grade ≥ 3 (36% vs 7%, p< 0.05) and Young grade > 1 (36% vs 17%, p< 0.001). Occurrence of delirium in the days after EEG was associated with a delta-predominant background (48% vs 15%, p = 0.001); absence of reactivity (39% vs 10%, p = 0.003), Synek grade ≥ 3 (42% vs 17%, p = 0.001) and Young grade >1 (58% vs 17%, p = 0.0001). Conclusions In this prospective cohort of 110 septic ICU patients, early standard EEG was significantly disturbed. Absence of EEG reactivity, a delta-predominant background, PDs, Synek grade ≥ 3 and Young grade > 1 at day 1 to 3 following admission were independent predictors of ICU mortality and were associated with occurence of delirium. ESZ and PDs, found in about 20% of our patients. Their prevalence could have been higher, with a still higher predictive value, if they had been diagnosed more thoroughly using continuous EEG.

Neuroanatomy and Physiology of Brain Dysfunction in Sepsis.

Sepsis-associated encephalopathy (SAE), a complication of sepsis, is often complicated by acute and long-term brain dysfunction. SAE is associated with electroencephalogram pattern changes and abnormal neuroimaging findings. The major processes involved are neuroinflammation, circulatory dysfunction, and excitotoxicity. Neuroinflammation and microcirculatory alterations are diffuse, whereas excitotoxicity might occur in more specific structures involved in the response to stress and the control of vital functions. A dysfunction of the brainstem, amygdala, and hippocampus might account for the increased mortality, psychological disorders, and cognitive impairment. This review summarizes clinical and paraclinical features of SAE and describes its mechanisms at cellular and structural levels.

Emerging drugs for the treatment of sepsis.

ABSTRACT Introduction: The incidence of sepsis, the systemic inflammatory response of the host to an infectious insult, has steadily increased over past decades. This trend is expected to continue. Sepsis is a leading cause of death and disability worldwide. Treatment relies on antibiotics associated to source control and supportive care. Major progress has been made in the understanding and overall management of sepsis. However, there is no specific treatment for sepsis. Areas covered: We searched PubMed and the ClinicalTrials.gov site for English language reports of phase II and III clinical trials pertaining to the field of sepsis. The current review provides a summary of promising candidate treatments for sepsis. We broadly separated candidate drugs into three distinct categories: Blood purification techniques, immunomodulatory drugs and treatments targeting other systems including the heart, the endothelium or coagulation. Expert opinion: Efforts to identify an efficient treatment for sepsis are hampered by the broad definition of the syndrome associated with major heterogeneity between patients affected by sepsis. The characterization of homogeneous groups of patients, through biological or clinical markers is unfortunately lacking. Current research remains active. Candidate drugs for sepsis include hemoperfusion with polymyxin B coated fibre devices, modulation of the immune system with treatments such as hydrocortisone, intravenous immunoglobulins, mesenchymal stem cells, GM-CSF or interferon gamma. Candidate drugs acting on the cardiovascular system include short acting beta 1 blockers, levosimendan or selepressin. Finally, promising strategies, involving monoclonal antibodies or protein antagonists, which selectively inhibit bacterial virulence factors are being assessed at the bedside. A much awaited and needed specific treatment for sepsis will hopefully soon emerge.

Brainstem response patterns in deeply-sedated critically-ill patients predict 28-day mortality

Background and purpose Deep sedation is associated with acute brain dysfunction and increased mortality. We had previously shown that early-assessed brainstem reflexes may predict outcome in deeply sedated patients. The primary objective was to determine whether patterns of brainstem reflexes might predict mortality in deeply sedated patients. The secondary objective was to generate a score predicting mortality in these patients. Methods Observational prospective multicenter cohort study of 148 non-brain injured deeply sedated patients, defined by a Richmond Assessment sedation Scale (RASS) <-3. Brainstem reflexes and Glasgow Coma Scale were assessed within 24 hours of sedation and categorized using latent class analysis. The Full Outline Of Unresponsiveness score (FOUR) was also assessed. Primary outcome measure was 28-day mortality. A “Brainstem Responses Assessment Sedation Score” (BRASS) was generated. Results Two distinct sub-phenotypes referred as homogeneous and heterogeneous brainstem reactivity were identified (accounting for respectively 54.6% and 45.4% of patients). Homogeneous brainstem reactivity was characterized by preserved reactivity to nociceptive stimuli and a partial and topographically homogenous depression of brainstem reflexes. Heterogeneous brainstem reactivity was characterized by a loss of reactivity to nociceptive stimuli associated with heterogeneous brainstem reflexes depression. Heterogeneous sub-phenotype was a predictor of increased risk of 28-day mortality after adjustment to Simplified Acute Physiology Score-II (SAPS-II) and RASS (Odds Ratio [95% confidence interval] = 6.44 [2.63–15.8]; p<0.0001) or Sequential Organ Failure Assessment (SOFA) and RASS (OR [95%CI] = 5.02 [2.01–12.5]; p = 0.0005). The BRASS (and marginally the FOUR) predicted 28-day mortality (c-index [95%CI] = 0.69 [0.54–0.84] and 0.65 [0.49–0.80] respectively). Conclusion In this prospective cohort study, around half of all deeply sedated critically ill patients displayed an early particular neurological sub-phenotype predicting 28-day mortality, which may reflect a dysfunction of the brainstem.

Neuroanatomy of Sepsis-Associated Encephalopathy

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.Originally published in the Annual Update in Intensive Care and Emergency Medicine 2017. The number of authors differs in the two versions due to constraints regarding the number of authors in the Annual Update in Intensive Care and Emergency Medicine. In the Annual Update version of the review, the three senior authors appear in the acknowledgement section. In the Critical Care version, these three senior authors appear as full authors of the manuscript. All authors helped draft and revise the manuscript for critical intellectual content.

Prognostic value of nocturnal hypoventilation in neuromuscular patients

In neuromuscular disease (NMD) patients, current guidelines recommend the initiation of home mechanical ventilation (HMV) in case of daytime hypercapnia or nocturnal desaturation as an indirect sign of hypoventilation. Transcutaneous capno-oximetry (TcCO2) enables the direct assessment of nocturnal hypercapnia; however the best cut-off value remains to be defined. We aimed to compare the prognostic value of several published definitions of nocturnal hypercapnia in a cohort of NMD patients. All consecutive TcCO2 recordings performed between 2010 and 2014 in unventilated adult NMD patients in a tertiary reference centre were retrospectively collected. Initiation of HMV and mortality were collected as outcomes of interest. 124 patients with normal daytime blood gazes were analysed (median age 39 [IQR 31-55] years; vital capacity 61% [43-82] of predicted). The prevalence of nocturnal hypercapnia ranged from 3% to 44%, depending on the definition. Over a median follow-up duration of 2.5 years [IQR 1.6-4.1], HMV was initiated for 51 patients, whilst 4 patients died. Nocturnal peak TcCO2 ≥49 mmHg was the best predictor of HMV initiation in the follow-up, being associated with a hazard ratio of 2.6 [95% CI 1.4-4.6] in a multivariate analysis adjusting for lung function parameters. Nocturnal TcCO2 identifies NMD patients at risk for subsequent need for HMV in the following few years, who were not identified by daytime blood gases or nocturnal oximetry. As a consequence, peak nocturnal TcCO2 ≥49 mmHg should be considered as one of the criteria to start HMV in patients with NMDs, along with symptoms of hypoventilation, daytime hypercapnia, abnormal nocturnal oximetry results, and a diminished level of forced vital capacity.

Haemodynamic response to crystalloids or colloids in shock: an exploratory subgroup analysis of a randomised controlled trial

Objective To compare the haemodynamic effect of crystalloids and colloids during acute severe hypovolaemic shock. Design Exploratory subgroup analysis of a multicentre randomised controlled trial (Colloids Versus Crystalloids for the Resuscitation of the Critically Ill, CRISTAL, ClinicalTrials.gov NCT00318942). Setting CRISTAL was conducted in intensive care units in Europe, North Africa and Canada. Participants Current analysis included all patients who had a pulmonary artery catheter in place at randomisation. 220 patients (117 received crystalloids vs 103 colloids) underwent pulmonary artery catheterisation. Intervention Crystalloids versus colloids for fluid resuscitation in hypovolaemic shock. Outcome measures Haemodynamic data were collected at the time of randomisation and subsequently on days 1, 2, 3, 4, 5, 6 and 7. Results Median cumulative volume of fluid administered during the first 7 days was higher in the crystalloids group than in the colloids group (3500 (2000–6000) vs 2500 (1000–4000) mL, p=0.01). Patients in the colloids arm exhibited a lower heart rate over time compared with those allocated to the crystalloids arm (p=0.014). There was no significant difference in Cardiac Index (p=0.053), mean blood pressure (p=0.4), arterial lactates (p=0.9) or global Sequential Organ Failure Assessment score (p=0.3) over time between arms. Conclusions During acute severe hypovolaemic shock, patients monitored by a pulmonary artery catheter achieved broadly similar haemodynamic outcomes, using lower volumes of colloids than crystalloids. The heart rate was lower in the colloids arm.