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Stress hyperglycemia and hyperlactatemia are commonly referred to as markers of stress severity and poor outcome in children with severe acute illness or febrile seizures. Our prospective study aimed to explore the risk factors for stress hyperglycemia and the predictive value of stress hyperglycemia for febrile seizure recurrence. We evaluated as risk factors for blood glucose level, serum lactate, acid—base status, and the clinical parameters relevant to the severity of the infectious context or to febrile seizure event: fever degree, fever duration, seizure type and aspect, seizure duration, and recurrence.
The comparison of the stress versus non-stress hyperglycemia groups revealed lower pH median interquartile range : 7. These findings suggest a particular acute stress reaction in febrile seizures, with stress hyperglycemia playing an important role, particularly in patients with a recurrent seizure pattern.
A more complex future approach linking pathogenic mechanisms and genetic traits would be advised and could provide further clues regarding recurrence pattern and individualized treatment. Febrile seizures are reported among stress-related conditions correlated with stress hyperglycemia. Stress hyperglycemia is defined as transient high blood glucose levels, with spontaneous resolution after the acute illness regresses [ 1 ]. The proposed triggering mechanisms in febrile seizures are temperature-sensitive ion channels and increased neuronal excitability in the context of proinflammatory cytokines [ 3 ].
Both seizure activity and fever-illness context have common stress-related mechanisms with high metabolic states, hypoperfusion, relative hypoxic states due to rising oxygen demands needed for additional energy supply, and accelerated glycolysis [ 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].
The oxidative stress is playing a key role as a common pathway for febrile seizures and stress hyperglycemia [ 8 , 12 , 13 ]. Moreover, in stress hyperglycemia, cytokines and hormones, interact in a complex manner supporting gluconeogenesis, glycogenolysis, and insulin resistance as pathogenic hallmarks [ 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ].
Further details on the endogenous mechanism of stress hyperglycemia are available in Figure A1 and the text in the Appendix A. In febrile seizures, the intricate interplay of the neuroendocrine catecholamines and immune system pathways are common grounds for stress hyperglycemia and hyperlactatemia Appendix A [ 1 , 4 , 11 ]. Most research reports suggest that stress hyperglycemia and hyperlactatemia are more than markers of stress severity and participate in the complex adaptive and protective stress-related mechanisms supporting the survival response of the host to stress [ 1 , 4 , 5 , 11 , 14 , 15 , 16 , 17 , 18 ].
During stress, proinflammatory cytokines modulate glycemia levels upregulating GLUT-1 and downregulating GLUT-4 plasma membrane glucose transporters improve the redistribution of glucose toward the central nervous system, macrophage rich tissues and immune system [ 5 ], and cellular glucose uptake [ 5 , 18 ].
More than a byproduct of anaerobiosis, the lactate emerges as an important gluconeogenetic precursor, energy source, and as a key player for adapting to stress-related conditions [ 19 , 20 ]. It seems that high levels of lactate might have a dual protective role during the initial stage and at the end of the seizure event in the context of metabolic acidosis [ 21 ]. Further details on the mechanism of neuroendocrine responses, stress hyperglycemia, hyperlactatemia, and the immune system responses in febrile seizures are available in Appendix A.
According to some other studies however, acute and long-term stress-induced hyperglycemia is currently believed to support a vicious cycle of self-promoting, exacerbating cytokine, inflammatory, and oxidative stress response [ 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Moreover, during febrile seizures, hyperlactatemia with or without acidosis reflects a complex metabolic disturbance, an imbalance between anaerobic and aerobic lactate production and clearance between the glycolytic and Krebs cycle activity either from the overproduction of pyruvate by increased glycolysis or from the underutilization of pyruvate, or from both [ 22 ].
In light of these reports, we aimed to explore, in a pilot study, the risk factors for stress hyperglycemia and stress hyperglycemia as a potential sensitive biomarker related to febrile seizure recurrence. Our main goal was to offer the practitioners a fast and easily accessible tool to assess the recurrence risk in febrile seizures. We evaluated the possible association of blood glucose levels with serum lactate, acid—base status, clinical parameters that define the severity of both infectious context, and febrile seizures fever degree, fever duration, seizure type and aspect, seizure duration, and recurrence.
We conducted a prospective study in the Pediatric Clinical Hospital from Sibiu, Romania between October and October , on children admitted with febrile seizures in the Emergency Department ED. Parents of all eligible children gave their informed consent for inclusion before they participated in the study.
The study was conducted in accordance with the Declaration of Helsinki and followed the principles of good clinical practice. The protocol was approved by the Ethics Committee of our institution. All the children presenting a characteristic and unequivocal history of a recent FS febrile seizure were included. The patients with central nervous system infections, other possible traumatic and metabolic causes of symptomatic seizures dyselectrolytemia, hypoglycemia , preceding afebrile seizures, a pre-existing history of diabetes, uncertain or incomplete clinical data were not considered for enrolment.
For children with recurrent febrile seizures, each seizure was treated as a distinct event, resulting in febrile seizure events.
We defined the cohort by applying the age criterion according to the revised ILAE International League of Epilepsy definition, namely age ranging between one month to five years [ 23 ]. A febrile context was documented if the temperature was higher than The simple febrile seizure was defined as a primary generalized seizure, lasting under 15 min and not recurring within 24 h.
The follow up period was 36 months. The follow up venous blood samples were taken up to 2 h after the seizure event. Blood glucose, lactate, and parameters defining acid—base status pH, pCO 2 , HCO 3 were documented for all venous blood samples. Current approaches envisage a cautionary view in evaluating the peripheral venous lactate instead of arterial lactate, especially for significant high value levels [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. However, recent reviews on lactate measurement arterial versus venous blood sampling revealed very strong correlations between arterial and venous lactate concentrations [ 32 ].
Moreover, venous blood gas sampling is also currently emerging as an alternative method for the acid—base status assessment pH, HCO 3 , pCO 2 levels.
A meta-analysis concluded a good pH and HCO 3 , but a less tighter pCO 2 correlation between venous and arterial blood [ 33 ].
From a clinical practice perspective, it is acknowledged to be a more convenient method [ 34 ]. We interpreted the laboratory data for peripheral venous blood gas referring to pH within the normal range of 7. According to our study design, the enrolled patients were evaluated with a focus on glycemic status, general patient characteristics, seizure activity, and acute illness characteristics.
Nutritional status was assessed using Word Health Organization growth charts weight for length referred to gender under two years of age and BMI for age and gender over two years of age [ 39 ]. We considered as potential predictors for glycemic status the variables age, gender, the body temperature at seizure onset, time interval between last fever episode and seizure onset, seizure duration, seizure types simple or complex febrile seizures , seizure semiology generalized or focal, with motor or non-motor characteristics , seizure recurrence, and multiple seizures within 24 h.
Seizure duration was defined in four categories as less than 1 min, 1—4. Time intervals from fever onset up to the seizure event and fever onset to fever remission were used as parameters for evaluating illness severity.
We computed the means, medians, and interquartile range for the two groups. Risk factor analysis for stress hyperglycemia was conducted using the multivariable logistic regression method.
All statistical analyses were performed using SPSS software Data analysis on the patients identified distinct febrile seizures events and 44 The mean age was From a nutritional status perspective comparing the two subgroups, in the non-stress hyperglycemia group According to the seizure semiology, the most common findings for febrile seizure events in the admitted patients were generalized Seizure duration between 1 and 5 min prevailed Prolonged seizures over 15 min, 3.
From 22 Most febrile seizures In cases Temperature normalization occurred within the first 24 h in Only five febrile seizures events were associated with prolonged fever over 72 h. There were 28 More than half of the febrile seizure events There were two patients with mild hypoglycemia, but not in the range of acute symptomatic seizure so we considered them eligible for our study.
Most patients had a rapid decline of stress hyperglycemia values, with normoglycemia reported at the up to two hours follow up from the admittance. Only two patients had a slower, but consistent glucose level decrease, reaching normal range up to 4 h. None of the patients from the intermediate and stress hyperglycemia groups was diagnosed with diabetes during the 36 months follow up.
The number of patients with stress hyperglycemia was significantly higher in the case of complex febrile seizure On the same note, there was a higher recurrence tendency in the stress hyperglycemia group Furthermore, in the stress hyperglycemia group, there was a shorter time interval, less than six hours between fever onset and seizure event The stress hyperglycemia group had lower pH 7.
Moreover, considering the three glycemic subcategories of normoglycemia vs. Comparison of characteristics for children with stress hyperglycemia versus non-stress hyperglycemia group.
We noticed a slightly higher prevalence of stress hyperglycemia in the febrile seizure cohort compared to the reports by Valerio et al.
The fast remission of stress hyperglycemia did not impose insulin therapy in our study group, as mentioned recently by Fattorusso et al. Emergency Department standards of care included non-glucose hydroelectrolytic solutions and antipyretic treatment. Although some pediatric studies involving patients with traumatic brain injury, sepsis, burns, surgical conditions have reported a better outcome in the group with strict glycemic control in comparison to the conventional approach, the results were inconsistent and were associated with a higher hypoglycemia risk.
Currently, tight glycemic control using insulin therapy is controversial and the optimum timing of insulin therapy and target blood glucose uncertain, due to the conflicting results of the available literature data [ 43 ]. The main findings in our study pointed out that glycemic levels were significantly higher in children with complex febrile seizures, mainly in prolonged febrile seizures over 15 min.
Seizure duration was directly correlated with an increase in blood glucose levels, supporting prolonged febrile seizure as risk factors for stress hyperglycemia.
The proposed mechanisms during prolonged seizures are related to aberrant, ongoing neuronal discharges leading to a high metabolic state, exacerbating aerobic glucose metabolism and anaerobic glycolysis [ 11 ].
The results are in accordance to Lee et al. The time interval up to six hours between fever onset and seizure event was observed in a higher proportion in the stress hyperglycemia group, invalidating the value of prolonged infectious context as a risk factor for stress hyperglycemia. A complex interplay between fever, seizure, and infection as combined stressors, triggering a cumulative, synergic interaction between proinflammatory cytokines and stress-related hormones interleukins, growth hormone, insulin, glucagon could offer a potential explanation Appendix A [ 42 ].
Moreover, other studies have reported higher stress hyperglycemia prevalence in febrile seizures in contrast to seizure events not precipitated by fever or by fever without seizure events [ 42 ]. Valerio et al. The results are in agreement with other findings correlating febrile seizures with hypocapnia and respiratory alkalosis through fever induced hyperventilation [ 45 , 46 ]. Lower seizure threshold of the brain receptors associated with alkalosis, and brain alkalosis as promoters of epileptic activity and enhancers of neuronal excitability have been proposed as possible seizure mechanisms [ 47 , 48 ].
The study identified an important association with statistical significance between hyperlactatemia and stress hyperglycemia. Our results are consistent with the current available literature data in febrile seizures. A complex interplay of the neuroendocrine catecholamine and immune system seems to be the common ground for stress hyperglycemia and hyperlactatemia.
In this context, high lactate levels might have a dual protective role in the initial stage and at the end of the seizure events in the context of metabolic acidosis. A transitory high metabolic demand, hypoperfusion, a relative hypoxic state due to rising oxygen demand needed for additional energy supply, and accelerated glycolysis are common stress related mechanisms for the fever-illness context and seizure activity [ 19 , 20 ].
Hyperlactatemia is acknowledged as the result of dysbalance between lactate production and lactate uptake and clearance mainly through the Cori cycle. In febrile seizures, two mechanisms determine an increase in lactate production namely accelerated aerobe glycolysis by catecholamine and anaerobe glycolysis by partial local muscle tissue hypoxia during massive increase in muscular activity. The systemic alkalosis demonstrated in our febrile seizure study group could explain the impaired lactate liver uptake with subsequent decreased lactate clearance [ 49 , 50 , 51 ].
Another known mechanism is stimulation of phosphofructokinase during alkalosis, promoting glycolysis and lactate production [ 52 ].
Furthermore, our study demonstrated a two times higher recurrence risk tendency in the stress hyperglycemia group compared to the non-stress hyperglycemia group.
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