Prognostic impact of hypernatremia for septic shock patients in the intensive care unit

Bernal A., Zafra M.A., Simón M.J., Mahía J.

Body sodium (Na) levels must be maintained within a narrow range for the correct functioning of the organism (Na homeostasis). Na disorders include not only elevated levels of this solute (hypernatremia), as in diabetes insipidus, but also reduced levels (hyponatremia), as in cerebral salt wasting syndrome. The balance in body Na levels therefore requires a delicate equilibrium to be maintained between the ingestion and excretion of Na. Salt (NaCl) intake is processed by receptors in the tongue and digestive system, which transmit the information to the nucleus of the solitary tract via a neural pathway (chorda tympani/vagus nerves) and to circumventricular organs, including the subfornical organ and area postrema, via a humoral pathway (blood/cerebrospinal fluid). Circuits are formed that stimulate or inhibit homeostatic Na intake involving participation of the parabrachial nucleus, pre-locus coeruleus, medial tuberomammillary nuclei, median eminence, paraventricular and supraoptic nuclei, and other structures with reward properties such as the bed nucleus of the stria terminalis, central amygdala, and ventral tegmental area. Finally, the kidney uses neural signals (e.g., renal sympathetic nerves) and vascular (e.g., renal perfusion pressure) and humoral (e.g., renin–angiotensin–aldosterone system, cardiac natriuretic peptides, antidiuretic hormone, and oxytocin) factors to promote Na excretion or retention and thereby maintain extracellular fluid volume. All these intake and excretion processes are modulated by chemical messengers, many of which (e.g., aldosterone, angiotensin II, and oxytocin) have effects that are coordinated at peripheral and central level to ensure Na homeostasis.

Xin Y., Tian M., Deng S., Li J., Yang M., Gao J., Pei X., Wang Y., Tan J., Zhao F., Gao Y., Gong Y.

Sepsis is a leading cause of intensive care unit admission and death worldwide. Most surviving patients show acute or chronic mental disorders, which are known as sepsis-associated encephalopathy (SAE). Although accumulating studies in the past two decades focused on the pathogenesis of SAE, a systematic review of retrospective studies which exclusively focuses on the inflammatory mechanisms of SAE has been lacking yet. This review summarizes the recent advance in the field of neuroinflammation and sheds light on the activation of microglia in SAE. Activation of microglia predominates neuroinflammation. As the gene expression profile changes, microglia show heterogeneous characterizations throughout all stages of SAE. Here, we summarize the systemic inflammation following sepsis and also the relationship of microglial diversity and neuroinflammation. Moreover, a collection of neuroinflammation-related dysfunction has also been reviewed to illustrate the possible mechanisms for SAE. In addition, promising pharmacological or non-pharmacological therapeutic strategies, especially those which target neuroinflammation or microglia, are also concluded in the final part of this review. Collectively, clarification of the vital relationship between neuroinflammation and SAE-related mental disorders would significantly improve our understanding of the pathophysiological mechanisms in SAE and therefore provide potential targets for therapies of SAE aimed at inhibiting neuroinflammation.

Rosenthal M.D., Vanzant E.L., Moore F.A.

The nutritional hallmark of chronic critical illness (CCI) after sepsis is persistent inflammation, immunosuppression, and catabolism syndrome (PICS), which results in global resistance to the anabolic effect of nutritional supplements. This ultimately leaves these patients in a downward phenotypic spiral characterized by cachexia with profound weakness, decreased capacity for rehabilitation, and immunosuppression with the propensity for sepsis recidivism. The persistent catabolism is driven by a pathologic low-grade inflammation with the inability to return to homeostasis and by ongoing increased energy expenditure. Better critical care support systems and advances in technology have led to increased intensive care unit (ICU) survival, but CCI due to PICS with poor long-term outcomes has emerged as a frequent phenotype among ICU sepsis survivors. Unfortunately, therapies to mitigate or reverse PICS-CCI are limited, and recent evidence supports that these patients fail to respond to early ICU evidence-based nutrition protocols. A lack of randomized controlled trials has limited strong recommendations for nutrition adjuncts in these patients. However, based on experience in other conditions characterized by a similar phenotype, immunonutrients aimed at counteracting inflammation, immunosuppression, and catabolism may be important for improving outcomes in PICS-CCI patients. This manuscript intends to review several immunonutrients as adjunctive therapies in treating PICS-CCI.

Hahn R.G., Patel V., Dull R.O.

The number of studies measuring breakdown products of the glycocalyx in plasma has increased rapidly during the past decade. The purpose of the present systematic review was to assess the current knowledge concerning the association between plasma concentrations of glycocalyx components and structural assessment of the endothelium.We performed a literature review of Pubmed to determine which glycocalyx components change in a wide variety of human diseases and conditions. We also searched for evidence of a relationship between plasma concentrations and the thickness of the endothelial glycocalyx layer as obtained by imaging methods.Out of 3,454 publications, we identified 228 that met our inclusion criteria. The vast majority demonstrate an increase in plasma glycocalyx products. Sepsis and trauma are most frequently studied, and comprise approximately 40 publications. They usually report 3-4-foldt increased levels of glycocalyx degradation products, most commonly of syndecan-1. Surgery shows a variable picture. Cardiac surgery and transplantations are most likely to involve elevations of glycocalyx degradation products. Structural assessment using imaging methods show thinning of the endothelial glycocalyx layer in cardiovascular conditions and during major surgery, but thinning does not always correlate with the plasma concentrations of glycocalyx products. The few structural assessments performed do not currently support that capillary permeability is increased when the plasma levels of glycocalyx fragments in plasma are increased.Shedding of glycocalyx components is a ubiquitous process that occurs during both acute and chronic inflammation with no sensitivity or specificity for a specific disease or condition.

Mutter C.M., Smith T., Menze O., Zakharia M., Nguyen H.

Bauer M., Groesdonk H.V., Preissing F., Dickmann P., Vogelmann T., Gerlach H.

Verschiedene Autoren diskutieren, ob fehlende Qualitätsinitiativen und Behandlungsstandards in Deutschland im internationalen Vergleich zu höherer Sterblichkeit bei Sepsis und septischem Schock führen könnten. Dem gegenüber steht eine international anerkannte intensivmedizinische Versorgung in Deutschland, z. B. während der COVID-19-Pandemie. Ziel dieser Studie war es, die Sterblichkeit bei Sepsis und septischem Schock in Deutschland zu ermitteln und mit anderen Industrienationen zu vergleichen. In eine systematischen Literaturrecherche wurden alle zwischen 2009 und 2020 veröffentlichten Interventions- und Beobachtungsstudien aus den Datenbanken PubMed und Cochrane Library eingeschlossen. Die 30- und 90-Tages-Sterblichkeit bei Sepsis und septischem Schock wurde in einer Metaanalyse mittels „Random-effects“-Modells gepoolt. Insgesamt wurden 134 Studien in die Meta-Analyse eingeschlossen. Die 30-Tages-Sterblichkeit bei Sepsis betrug in Deutschland 26,50 % (95 %-KI: 19,86–33,15 %), in Europa (ohne Deutschland) 23,85 % (95%-KI: 20,49–27,21 %) und in Nordamerika 19,58 % (95%-KI: 14,03–25,14 %). Die 30-Tages-Sterblichkeit bei septischem Schock betrug 30,48 % (95 %-KI: 29,30–31,67 %), 34,57 % (95 %-KI: 33,51–35,64 %) bzw. 33,69 % (95 %-KI: 31,51–35,86 %). Die 90-Tages-Sterblichkeit bei septischem Schock betrug 38,78 % (95 %-KI: 32,70–44,86 %), 41,90 % (95 %-KI: 38,88–44,91 %) beziehungsweise 34,41 % (95 %-KI: 25,66–43,16 %). Es ergaben sich somit keine Anhaltspunkte dafür, dass die Sterblichkeit bei Sepsis/septischem Schock im internationalen Vergleich in Deutschland erhöht ist.

Olsen M.H., Møller M., Romano S., Andersson J., Mlodzinski E., Raines N.H., Sherak R., Jeppesen A.N.

Describe the relationship between ICU-acquired hypernatremia and in-hospital mortality and investigate the optimal hypernatremia correction rate.Observational study including two individual ICU cohorts. We used the Medical Information Mart for Intensive Care III v. 1.4 database consists of all ICU patients admitted to the Beth Israel Deaconess Medical Center in Boston from 2001 to 2012 (n = 46,476). The electronic ICU v. 2.0 database consists of all ICU patients admitted to 208 distinct hospitals across the United States from 2014 to 2015 (n = 200,859). We included all adult patients admitted to an ICU with two consecutive sodium samples within normal range (135-145 mmol/L) and without two consecutive hyponatremic samples (< 135 mmol/L) during the ICU stay.Of 23,445 patients identified in Medical Information Mart for Intensive Care III, 9% (n = 2,172) developed hypernatremia during their ICU stay. In electronic ICU, 88,160 patients were identified and 7% (n = 5,790) developed hypernatremia. In both cohorts, patients with hypernatremia had a higher mortality (Medical Information Mart for Intensive Care III: 20% vs 42%; p < 0.01 and electronic ICU: 6% vs 22%; p < 0.01), with hypernatremia increasing the risk of in-hospital mortality (Medical Information Mart for Intensive Care III: odds ratio, 1.15; 95% CI, 1.13-1.17 and electronic ICU: odds ratio, 1.11; 95% CI, 1.10-1.12) and over time using a Cox regression. Rapid sodium correction rate (> 0.5 mmol/L/hr) was associated with an increased in-hospital mortality in both cohorts (Medical Information Mart for Intensive Care III: odds ratio, 1.08; 95% CI, 1.03-1.13 and electronic ICU: odds ratio, 1.10; 95% CI, 1.06-1.13). In the electronic ICU cohort, rapid correction rates were associated with a significant difference in in-hospital mortality, but there was no statistically significant association in the Medical Information Mart for Intensive Care III cohort.ICU-acquired hypernatremia is associated with increased in-hospital mortality. Furthermore, a rapid sodium correction rates may be harmful. This suggests it is important to both prevent ICU-acquired hypernatremia and to avoid rapid correction rates if a patient becomes hypernatremic.

Cox M.C., Brakenridge S.C., Stortz J.A., Hawkins R.B., Darden D.B., Ghita G.L., Mohr A.M., Moldawer L.L., Efron P.A., Moore F.A.

As hospital sepsis mortality has decreased, more surgical ICU survivors are progressing into chronic critical illness (CCI). This study documents the incidence of CCI and long-term outcomes of patients with abdominal sepsis. We hypothesized that patients developing CCI would have biomarker evidence of immune and metabolic derangement, with a high incidence of poor 1-year outcomes.Review of abdominal sepsis patients entered in a prospective longitudinal study of surgical ICU sepsis.Of the 144 study patients, only 6% died early, 37% developed CCI (defined as ICU days ≥14 with organ dysfunction) and 57% were classified rapid recovery (RAP). Compared to RAP, CCI patients a) were older (66 vs 58), males who were sicker at baseline (Charlson Comorbidity Index 4 vs 2), b) had persistently elevated biomarkers of dysregulated immunity/metabolism (IL-6, IL-8, sPDL-1, GLP1), c) experienced more secondary infections (4.9 vs 2.3) and organ failure (Denver MOF frequency 40 vs 1%), d) were much more likely to have poor dispositions (85 vs 22%) with severe persistent disabilities by Zubrod Score and e) had a notably higher 1-year mortality of 42% (all p < 0.05).Over 1/3rd surgical ICU patients treated for abdominal sepsis progress into CCI and experience dismal long-term outcomes.

Rugg C., Ströhle M., Treml B., Bachler M., Schmid S., Kreutziger J.

Developing hypernatremia while on intensive care unit (ICU) is a common problem with various undesirable effects. A link to persistent inflammation, immunosuppression and catabolism syndrome (PICS) can be established in two ways. On the one hand, hypernatremia can lead to inflammation and catabolism via hyperosmolar cell stress, and on the other, profound catabolism can lead to hypernatremia via urea-induced osmotic diuresis. In this retrospective single-center study, we examined 115 patients with prolonged ICU stays (≥14 days) and sufficient renal function. Depending on their serum sodium concentrations between ICU day 7 and 21, allocation to a hypernatremic (high) and a nonhypernatremic group (low) took place. Distinct signs of PICS were detectable within the complete cohort. Thirty-three of them (28.7%) suffered from ICU-acquired hypernatremia, which was associated with explicitly higher signs of inflammation and ongoing catabolism as well as a prolonged ICU length of stay. Catabolism was discriminated better by the urea generation rate and the urea-to-creatinine ratio than by serum albumin concentration. An assignable cause for hypernatremia was the urea-induced osmotic diuresis. When dealing with ICU patients requiring prolonged treatment, hypernatremia should at least trigger thoughts on PICS as a contributing factor. In this regard, the urea-to-creatinine ratio is an easily accessible biomarker for catabolism.

Broll M., John S.

Die Hypernatriämie ist eine häufige Elektrolytstörung im klinischen Alltag. Auslöser ist in vielen Fällen ein Wassermangel oder eine erhöhte Salzzufuhr. Bei außerhalb des Krankenhauses erworbenen Hypernatriämien ist die Ursache meist ein erhöhter Wasserverlust oder eine verminderte Wasserzufuhr. Davon abzugrenzen sind nosokomiale Hypernatriämien, die durch eine inadäquate Flüssigkeitsbilanzierung, medikamentöse Salzüberlastung oder osmotische Diurese verursacht sind. Wichtigste Komplikation einer akuten Hypernatriämie ist die Zellschrumpfung. Eine chronische Hypernatriämie betrifft alle Zellfunktionen mit vorwiegend zerebralen Symptomen bis hin zum Koma; Hauptkomplikation ist hier der zu schnelle Ausgleich einer adaptierten Elektrolytstörung mit Entwicklung eines Hirnödems. Veränderungen, die auch die Gesamtosmolalität beeinflussen, müssen berücksichtigt und die Gesamtosmolalität stets langsam ausgeglichen werden. Bei unklarer Dauer ist immer von einer chronischen Störung auszugehen.

Natochin Y.V., Golosova D.V.

In mammals, three subtypes of V-receptors have been identified in the kidney. The effects of vasopressin, a hormone synthesized in the hypothalamus, are triggered by three distinct receptor isoforms: V2, V1a, and V1b. Stimulation of V2-receptors regulates urine osmotic concentration by increasing sodium reabsorption in the thick ascending limb of the loop of Henle and enhancing osmotic permeability of the epithelium cells in the collecting duct. Stimulation of V1a-receptors inhibits renal sodium reabsorption and induces natriuresis, comparable to the effect of the diuretic furosemide, in the thick ascending limb of the loop of Henle. Stimulation of V1b-receptors induces potassium secretion in the final parts of the distal segments and initial parts of the collecting ducts. In this review, we discuss the role of vasopressin and its interaction with V-receptor subtypes in natriuresis and for stabilizing the physicochemical parameters of the internal environment and water-salt homeostasis in humans. A better understanding of these systems and their regulation is necessary to facilitate identification of additional system components and mechanisms, clarify their contribution during various normal and pathological functional states, and suggest novel strategies for the development of therapeutic interventions.

Rudd K.E., Johnson S.C., Agesa K.M., Shackelford K.A., Tsoi D., Kievlan D.R., Colombara D.V., Ikuta K.S., Kissoon N., Finfer S., Fleischmann-Struzek C., Machado F.R., Reinhart K.K., Rowan K., Seymour C.W., et. al.

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates.In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia.Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa.The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

Hesselink L., Hoepelman R.J., Spijkerman R., de Groot M.C., van Wessem K.J., Koenderman L., Leenen L.P., Hietbrink F.

Nowadays, more trauma patients develop chronic critical illness (CCI), a state characterized by prolonged intensive care. Some of these CCI patients have disproportional difficulties to recover and suffer from recurrent infections, a syndrome described as the persistent inflammation, immunosuppression and catabolism syndrome (PICS). A total of 78 trauma patients with an ICU stay of ≥14 days (CCI patients) between 2007 and 2017 were retrospectively included. Within this group, PICS patients were identified through two ways: (1) their clinical course (≥3 infectious complications) and (2) by laboratory markers suggested in the literature (C-reactive protein (CRP) and lymphocytes), both in combination with evidence of increased catabolism. The incidence of PICS was 4.7 per 1000 multitrauma patients. The sensitivity and specificity of the laboratory markers was 44% and 73%, respectively. PICS patients had a longer hospital stay (median 83 vs. 40, p < 0.001) and required significantly more surgical interventions (median 13 vs. 3, p = 0.003) than other CCI patients. Thirteen PICS patients developed sepsis (72%) and 12 (67%) were readmitted at least once due to an infection. In conclusion, patients who develop PICS experience recurrent infectious complications that lead to prolonged hospitalization, many surgical procedures and frequent readmissions. Therefore, PICS forms a substantial burden on the patient and the hospital, despite its low incidence.

Sakamoto A., Hoshino T., Boku K., Hiraya D., Inoue Y.

Hypernatremia due to salt poisoning is clinically rare and standard care procedures have not been established. We report a case of salt poisoning due to massive intake of seasoning soy sauce.A 40-year-old woman presented to the emergency department with seizures and remarkable hypernatremia with a serum sodium concentration of 183 mEq/L. The initial brain computed tomography scan showed brain shrinkage, which could occur during the acute phase of hypernatremia. We reduced her serum sodium level rapidly, rather than at the recommended slow rate. On day 3, the patient's brain computed tomography scan showed widespread low-density areas and edema. The patient died 8 days after admission.After reviewing instances of resuscitation following salt intoxication, aggressive rapid correction of serum sodium concentration should only be considered in acute phases of hypernatremia within a few hours from ingestion, and 2-3 h could be one of the criteria.

Wenstedt E.F., Verberk S.G., Kroon J., Neele A.E., Baardman J., Claessen N., Pasaoglu Ö.T., Rademaker E., Schrooten E.M., Wouda R.D., de Winther M.P., Aten J., Vogt L., Van den Bossche J.

Inflammation may play a role in the link between high salt intake and its deleterious consequences. However, it is unknown whether salt can induce proinflammatory priming of monocytes and macrophages in humans. We investigated the effects of salt on monocytes and macrophages in vitro and in vivo by performing a randomized crossover trial in which 11 healthy human subjects adhered to a 2-week low-salt and high-salt diet. We demonstrate that salt increases monocyte expression of CCR2, a chemokine receptor that mediates monocyte infiltration in inflammatory diseases. In line with this, we show a salt-induced increase of plasma MCP-1, transendothelial migration of monocytes, and skin macrophage density after high-salt diet. Macrophages demonstrate signs of an increased proinflammatory phenotype after salt exposure, as represented by boosted LPS-induced cytokine secretion of IL-6, TNF, and IL-10 in vitro, and by increased HLA-DR expression and decreased CD206 expression on skin macrophages after high-salt diet. Taken together, our data open up the possibility for inflammatory monocyte and macrophage responses as potential contributors to the deleterious effects of high salt intake.