Review
Treatment of hyperglycemia in patients with acute stroke
Tratamiento de la hiperglucemia en pacientes con ictus agudo
a Servicio de Medicina Interna, Hospital de la Merced, Osuna, Sevilla, Spain
b Servicio de Neurología, Hospital de Valme, Universidad de Sevilla, Sevilla, Spain
c Institute of Primary Care & Public Health, Cardiff University School of Medicine, WCAT Lead – Geriatric & Stroke Medicine, Cardiff, United Kingdom
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Heart Failure</span>" "titulo" => "Target organ damage in acute heart failure" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "99" "paginaFinal" => "105" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Lesión de órganos diana en la insuficiencia cardiaca aguda" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1061 "Ancho" => 1618 "Tamanyo" => 134385 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Pathophysiology of acute heart failure. <span class="elsevierStyleItalic">Abbreviations</span>: ALT, alanine aminotransferase; <span class="elsevierStyleItalic">AST</span>, aspartate aminotransferase.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. 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(a) The patient has to rearrange the colored tiles using the first and last of each row as reference. (b) The result of a healthy individual. (c) The result of a patient with achromatopsia, the black lines indicate the percentage of error in the placement of each tile. This test can be performed for free at the website <a class="elsevierStyleInterRef" id="intr0005" href="http://www.color-blindness.com/">http://www.color-blindness.com</a>.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "R. Álvarez, J. Masjuan" "autores" => array:2 [ 0 => array:2 [ "nombre" => "R." "apellidos" => "Álvarez" ] 1 => array:2 [ "nombre" => "J." 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Castilla-Guerra, M.C. Fernández-Moreno, J. Hewitt" "autores" => array:3 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "Castilla-Guerra" "email" => array:1 [ 0 => "castillafernandez@hotmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "M.C." "apellidos" => "Fernández-Moreno" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "J." "apellidos" => "Hewitt" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Hospital de la Merced, Osuna, Sevilla, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Neurología, Hospital de Valme, Universidad de Sevilla, Sevilla, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Institute of Primary Care & Public Health, Cardiff University School of Medicine, WCAT Lead – Geriatric & Stroke Medicine, Cardiff, United Kingdom" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento de la hiperglucemia en pacientes con ictus agudo" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A 70-year-old man with a history of cholecystectomy and arterial hypertension for the last 10 years, undergoing treatment with enalapril 20<span class="elsevierStyleHsp" style=""></span>mg daily and with no known diabetes mellitus, was taken to hospital because when his wife woke him, his speech was incoherent and he lacked strength on the right side of the body. A cranial computed tomography was performed in the emergency department, which revealed an extensive infarction in the territory of the left middle cerebral artery. The laboratory tests on admission showed glycemia levels of 172<span class="elsevierStyleHsp" style=""></span>mg/dL.</p><p id="par0010" class="elsevierStylePara elsevierViewall">What is the best strategy for treating hyperglycemia in such a patient, and what evidence is there on this subject?</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">The clinical problem</span><p id="par0015" class="elsevierStylePara elsevierViewall">Stroke is a health problem of considerable importance, whose incidence is growing rapidly worldwide. In Spain, stroke is the main cause of death among women and the second, after ischemic heart disease, for men.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">1</span></a> According to the most recent data from the Survey on Hospital Morbidity of the National Institute of Statistics, there were 118,308 admissions in 2013 for cerebrovascular disease.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a> In the last 15 years, the number of patients treated for cerebrovascular disorders in hospitals of the Spanish National Health System has increased more than 40%.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Moreover, diabetes is a highly and increasingly prevalent disease in the adult population. In Spain alone, more than 5 million people (13.8% of the population) are affected by the disease, almost half of whom are unaware that they have it.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Patients with diabetes have an increased risk of stroke, particularly ischemic.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">5</span></a> It is estimated that diabetes increases the risk of stroke 2–3 fold for men and 2–5 fold for women. A recent meta-analysis on more than 775,385 individuals has confirmed that the excess risk of stroke associated with diabetes is significantly greater in women than in men (27% more), regardless of the sex differences in other cardiovascular risk factors.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a> The risk of ischemic stroke is increased by 3% for every year that a patient has diabetes.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Therefore, the proportion of patients with diabetes who are hospitalized for stroke has been increasing in recent years, and currently represent a third of those hospitalized for stroke.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">8</span></a> The prognosis for stroke in patients with diabetes is also poorer. Hospital mortality (including long-term), risk of stroke recurrence, hospital stay and neurological and functional disability at discharge are all greater for patients with diabetes.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">9,10</span></a> Therefore, a greater understanding of the approach to hyperglycemia for patients with acute stroke is essential for providing better care for these patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Hyperglycemia in the acute phase of stroke</span><p id="par0035" class="elsevierStylePara elsevierViewall">Hyperglycemia is common in patients with acute stroke. In 2 studies, up to 40% and 50% of patients had hyperglycemia, respectively, many of whom had no history of diabetes mellitus.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">9,11</span></a> According to studies that continuously monitored glycemia levels, there are 2 phases of poststroke hyperglycemia: an early phase during the first 8<span class="elsevierStyleHsp" style=""></span>h, which occurs in 100% of patients with diabetes and in 50% of patients without diabetes; and a second later phase, 48<span class="elsevierStyleHsp" style=""></span>h after the stroke, which occurs in 78% of patients with diabetes and 27% of patients without diabetes.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">12</span></a> Therefore, a high glucose concentration during the acute phase of a stroke does not help differentiate between “stress hyperglycemia” and an increase in glycemia levels in patients with prediabetes or established diabetes, whether or not it was previously known.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The stress reaction that induces hyperglycemia is produced by both the activation of hypothalamic–pituitary–adrenal axis, which results in the secretion of high quantities of glucocorticoids (cortisol), and by the activation of the sympathetic autonomic nervous system. The increase in stress hormone levels stimulates the production of glucose by glycogenolysis, gluconeogenesis, proteolysis and lipolysis. The increase in adrenaline also contributes to insulin resistance and hyperinsulinemia.<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">13,14</span></a> Moreover, the damage to certain areas of the brain, such as the insular and opercular parts of the right hemisphere, promotes hyperglycemia, possibly by disinhibiting the sympathetic flow.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The reactive increase in glucose levels is not trivial, but rather, as shown in numerous studies, there is an association between the hyperglycemia of an ischemic stroke at admission and a poorer prognosis. This prognosis is affected by a poorer response to fibrinolytic treatment and a larger volume of the infarction area (measured by magnetic resonance imaging), among other reasons.<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">10,11,14,16</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The Glycemia in Acute Stroke (GLIAS) study performed in Spain, which included 476 patients with cerebral infarction of less than 24<span class="elsevierStyleHsp" style=""></span>h of evolution, determined that the threshold level of capillary glycemia that resulted in a poorer evolution was 155<span class="elsevierStyleHsp" style=""></span>mg/dL. Patients who reach this level within the first 48<span class="elsevierStyleHsp" style=""></span>h of the cerebral infarction have a 2.7-fold greater risk of death or dependence at 3 months, regardless of age, the presence of previous diabetes, the infarct volume and stroke severity.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">17</span></a> The prognostic value of hyperglycemia after the first 48<span class="elsevierStyleHsp" style=""></span>h and its causal relationship with the outcome are less clear.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Treatment of hyperglycemia in the acute phase of stroke</span><p id="par0055" class="elsevierStylePara elsevierViewall">The observed relationship between hyperglycemia and the poorer prognosis in patients with stroke leads us to ask whether its correction using hypoglycemic treatment can improve the prognosis. The main clinical trials that have explored the efficacy of hyperglycemia treatment in acute stroke have focused more on intensive insulin treatment (IIT) than on conventional treatment with insulin. The preference for the IIT of hyperglycemia in patients with acute stroke is based on the first studies performed with patients treated in intensive care units (ICUs), which initially appeared to favor its use in reducing mortality and complications.<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">11,14</span></a> However, a number of subsequent studies have not been able to confirm these conclusions. It has even been shown that IIT, when compared with conventional insulin therapy, increased mortality in critically ill patients.<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">19</span></a> A systematic review of 21 trials of IIT in hospitalized patients, which included conditions such as hospitalization in the ICU, perioperative care, acute myocardial infarction, stroke and other brain lesions, concluded that there was no consistent evidence demonstrating that strict glycemia control improved the prognosis when compared with less strict control. On the contrary, IIT was associated with an 6-fold higher increase in the risk of severe hypoglycemia.<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">20</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">There are numerous randomized clinical trials (RCTs) that have assessed the efficacy of correcting hyperglycemia in acute stroke (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). Many of these studies included only a small number of patients. The conclusions on the clinical efficacy of IIT were therefore not definitive.<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">21–26</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">The Glucose Insulin in Stroke Trial UK (GIST-UK),<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">22</span></a> the largest RCT that included 933 patients, was not able to demonstrate any clinical benefit with IIT. However, this study has been criticized for methodological problems that limit the value of its results. For example, most of the patients included in the trial showed no hyperglycemia, and the reduction in glycemia levels in the intensive treatment group was only 0.6<span class="elsevierStyleHsp" style=""></span>mmol/L less than that of the conventional treatment group.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Several meta-analyses have compared the effect of IIT to conventional insulin therapy. The first meta-analysis of 7 RCTs,<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">27</span></a> which included 1296 patients with acute stroke, found no benefit with IIT (odds ratio [OR] 1.0; 95% confidence interval [95% CI] 0.8–1.3). The risk of symptomatic hypoglycemia was significantly increased with IIT (OR 25.9; 95% CI 9.2–72.7). It is important to note that the results of this meta-analysis were highly influenced by the 933 participants from GIST-UK.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The second meta-analysis,<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">28</span></a> which included 9 studies with 1491 patients, also found statistically significant differences in mortality (OR 1.16; 95% CI 0.89–1.49) and the functional prognosis (OR 1.01; 95% CI 0.81–1.26). Similarly, the rate of hypoglycemia (OR 8.19; 95% CI 5.60–11.98) and the rate of symptomatic hypoglycemia (OR: 6.15; 95% CI 1.88–20.15) were higher among the patients treated with IIT.</p><p id="par0080" class="elsevierStylePara elsevierViewall">A recent update<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">29</span></a> of the first meta-analysis, which included 11 RCTs with 1583 participants (791 participants in the intervention group and 792 in the control group), also found no differences between the treatment and control groups in terms of mortality and dependence (OR 0.99; 95% CI 0.79–1.23) and final neurological deficit (OR 0.09; 95% CI: −0.19–0.01). The rate of symptomatic hypoglycemia, in contrast, was higher in the intervention group (OR 14.6; 95% CI 6.6–32.2).</p><p id="par0085" class="elsevierStylePara elsevierViewall">We can conclude that there is no evidence that intravenous IIT (administered to maintain the glycemia level within a specific range during the first hours of the acute ischemic stroke) provides benefits in terms of mortality or neurological deficit, while significantly increasing the number of hypoglycemic episodes.</p><p id="par0090" class="elsevierStylePara elsevierViewall">A new controlled RCT is currently underway (the <span class="elsevierStyleItalic">Stroke Hyperglycemia Insulin Network Effort</span> [SHINE] study),<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">30</span></a> which plans to include 1400 patients with acute stroke of less than 12<span class="elsevierStyleHsp" style=""></span>h of evolution with hyperglycemia. The study will compare standard therapy with subcutaneous insulin (with a blood glucose target of 80–179<span class="elsevierStyleHsp" style=""></span>mg/dL) against continuous intravenous insulin infusion (with a glycemia target of 80–130<span class="elsevierStyleHsp" style=""></span>mg/dL) for a maximum of 72<span class="elsevierStyleHsp" style=""></span>h. It is possible that its results will help clarify the benefits and risks of intensive glycemia control during the acute phase of stroke.</p><p id="par0095" class="elsevierStylePara elsevierViewall">It is also not clear that the conventional treatment of diabetes manages to adequately reduce glycemia levels, a goal that might be difficult in the first days of the stroke.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a> In fact, the GLIAS study showed that only 25% of the patients with acute cerebral infarction developed persistent hyperglycemia in the first 48<span class="elsevierStyleHsp" style=""></span>h and that conventional treatment was not able to control hyperglycemia in 40% of the cases.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">17</span></a> Despite the lack of evidence, however, the various guidelines for managing patients with stroke recommend treating the hyperglycemia of patients with acute stroke, especially patients with diabetes (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Moreover, it is speculated that oral diabetes drugs (ODD) have a possible neuroprotective effect in acute stroke. A number of observational studies have suggested that patients who have been taking these agents and experience a stroke have better neurological and functional outcomes at discharge.<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">31</span></a> Therefore, the possible neuroprotective role of ODDs is currently the subject of study, mainly in animal models where these drugs seem to have a neuroprotective action independent of their hypoglycemic action. Thus, the administration of sulfonylureas following a stroke reduces the infarct size and mortality, mainly by preventing cerebral edema.<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">32</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Dipeptidyl-peptidase-4 inhibitors, such as linagliptin, seem to decrease the size of the acute cerebral infarction (both in diabetic and nondiabetic mice) by a glucose-independent pathway, which probably involves the action of the glucagon-like peptide-1 (GLP-1).<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">33</span></a> In the case of metformin, a facilitator effect for poststroke recovery through improved angiogenesis has been suggested, an effect that would be mediated by the expression of the adenosine monophosphate-activated protein kinase.<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">34</span></a> Despite these interesting preclinical findings that suggest neuroprotective effects for ODDs in acute stroke, the clinical validity of ODDs for patients with acute stroke has yet to be demonstrated.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis of hyperglycemia in the acute phase of stroke</span><p id="par0110" class="elsevierStylePara elsevierViewall">As has already been stated, hyperglycemia is common in the acute phase of stroke. In a portion of these patients, the hyperglycemia reflects prediabetes or pre-existing diabetes, frequently not known previously. However, in the other patients, the hyperglycemia is due to a stress response, commonly known as “stress hyperglycemia”.</p><p id="par0115" class="elsevierStylePara elsevierViewall">Stress hyperglycemia is defined by glycemia levels under fasting conditions ≥126<span class="elsevierStyleHsp" style=""></span>mg/dL or a concentration >200<span class="elsevierStyleHsp" style=""></span>mg/dL, measured at any time, which occurs in a hospitalized patient with no prior history of diabetes and who spontaneously returns to the normal range after discharge.<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">35</span></a> Therefore, glucose levels at admission do not help differentiate between stress hyperglycemia and that produced in patients with pre-existing diabetes or prediabetes. Nevertheless, it is important to identify patients with prediabetes or diabetes in order to start secondary prevention measures and avoid the onset of a new stroke and the complications associated with glucose metabolism disorders.</p><p id="par0120" class="elsevierStylePara elsevierViewall">There are several methods for identifying individuals with prediabetes or diabetes, such as repeated measurements of plasma glucose levels under fasting conditions, the oral glucose tolerance test (OGTT) and the glycated hemoglobin concentration (HbA1c). However, the correlation among these tests is not 100%.</p><p id="par0125" class="elsevierStylePara elsevierViewall">In the context of patients with acute stroke, a high HbA1c concentration helps identify patients with prediabetes (HbA1c, 5.7–6.4%) or diabetes (HbA1c<span class="elsevierStyleHsp" style=""></span>≥<span class="elsevierStyleHsp" style=""></span>6.5%) who have not been previously diagnosed.<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">11,14</span></a> In a follow-up study of the National Health and Nutrition Examination Surveys 1999–2010, which included 1070 adults who had experienced a stroke, the HbA1c reading helped determine a prevalence of diabetes of 3.7% and a prevalence of prediabetes of 32.3%, both previously unknown.<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">36</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The combination of several of these methods, such as OGTT and HbA1c concentration, increases the sensitivity for detecting patients with an abnormal glucose metabolism. In a study on 269 patients with transient ischemic attacks (TIA), 374 with ischemic stroke and 57 with intracerebral hemorrhaging, all of whom had no history of diabetes, the combined analysis of the plasma glucose under fasting conditions, OGTT and HbA1c concentration helped identify 365 patients (52%) as having prediabetes and 188 (27%) as having diabetes.<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">37</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A number of authors have recommended repeating OGTT 3 months after the stroke to study the persistence of the glucose metabolism disorders,<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">38,39</span></a> given that between 26% and 71% of patients have impaired glucose tolerance that persists to 3 months, and between 4% and 42% progress to diabetes.<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">39</span></a> It has also been suggested that a pathological OGTT is correlated with an increased cardiovascular risk, given the greater contribution of postprandial glucose to subclinical inflammation and to insulin resistance, considered the most important pathogenic risk factor in type 2 diabetes.<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">40</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Although there is no unanimity concerning the technique to be employed or the moment to perform it, current clinical practice guidelines recommend that, after a TIA or ischemic stroke, all patients should undergo screening to rule out diabetes.<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">41,42</span></a> The current recommendations for studying glucose metabolism disorders in patients with ischemic stroke are summarized in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusions</span><p id="par0145" class="elsevierStylePara elsevierViewall">The patient was initially treated with 6<span class="elsevierStyleHsp" style=""></span>IU of rapid insulin in the emergency department and with a regular insulin regimen administered every 6<span class="elsevierStyleHsp" style=""></span>h for the first 24<span class="elsevierStyleHsp" style=""></span>h. Glycemic control was maintained within the limits of normal after the first 24<span class="elsevierStyleHsp" style=""></span>h. The HbA1c level was 5.5%. At 3 months, the laboratory tests and OGTT were repeated, with results within normal. The previous hyperglycemia was classified as stress hyperglycemia.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Although hyperglycemia in the acute phase of stroke is associated with a poor prognosis, there are still numerous issues still to be solved and that are the subject of debate in terms of the diagnostic and therapeutic aspects. We still do not know how long strict glycemia control should be maintained after a stroke, what insulin regimen should be used, what plasma glucose concentration should be achieved or what the importance is of the stroke subtype for deciding the treatment for the hyperglycemia. New studies currently underway, such as the SHINE study, might help clarify how to treat hyperglycemia in these patients.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres611132" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec625121" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres611133" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec625122" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "The clinical problem" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Hyperglycemia in the acute phase of stroke" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Treatment of hyperglycemia in the acute phase of stroke" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosis of hyperglycemia in the acute phase of stroke" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec625121" "palabras" => array:6 [ 0 => "Hyperglycemia" 1 => "Diabetes" 2 => "Acute stroke" 3 => "Insulin" 4 => "Diagnosis" 5 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec625122" "palabras" => array:6 [ 0 => "Hiperglucemia" 1 => "Diabetes" 2 => "Ictus agudo" 3 => "Insulina" 4 => "Diagnóstico" 5 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The proportion of diabetic patients who are hospitalized for stroke has been increasing in recent years, currently reaching almost a third of all cases of stroke. In addition, about half of patients with acute stroke present hyperglycemia in the first hours of the stroke.</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Although hyperglycemia in the acute phase of stroke is associated with a poor prognosis, its treatment is currently a topic of debate. There is no evidence that the adminstration of intravenous insulin to these patients offers benefits in terms of the evolution of the stroke. New studies in development, such as the SHINE study (Stroke Hyperglycemia Insulin Network Effort), may contribute to clarifying the role of intensive control of glycemia during the acute phase of the stroke.</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Ultimately, patients who have presented with stroke should be screened for diabetes.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">La proporción de pacientes diabéticos hospitalizados por ictus ha ido aumentando en los últimos años, alcanzando en la actualidad casi un tercio de todos los ictus. Además, prácticamente la mitad de los enfermos con ictus agudo pueden presentar hiperglucemia en las primeras horas del evento.</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A pesar de que la hiperglucemia en la fase aguda del ictus se asocia a un peor pronóstico, su tratamiento es en la actualidad motivo de controversia. No existen evidencias de que la administración de insulina por vía intravenosa en estos pacientes proporcione beneficios en la evolución del ictus. Nuevos estudios en desarrollo, como el estudio Stroke Hyperglycemia Insulin Network Effort (SHINE), posiblemente contribuyan a aclarar el papel del control intensivo de la glucemia durante la fase aguda del ictus.</p><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Finalmente, los pacientes que han presentado un ictus deberían ser sometidos a un cribado de diabetes.</p></span>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Castilla-Guerra L, Fernández-Moreno MC, Hewitt J. Tratamiento de la hiperglucemia en pacientes con ictus agudo. Rev Clin Esp. 2016;216:92–98.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">IIT, intensive insulin therapy.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Study \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Year \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Population \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Intervention \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Assessment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Result \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Vinychuk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2005 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ischemic stroke <12<span class="elsevierStyleHsp" style=""></span>h; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>128 (61 interventions, 67 controls) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous intravenous insulin infusion (glucose objective <7<span class="elsevierStyleHsp" style=""></span>mmol/L); checks every 4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Reduction in the plasma glucose concentration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Significant improvement in neurological state in the intervention group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.05). No hypoglycemia recordings \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GIST-UK \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2007 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">All types of stroke; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>933 (464 interventions, 469 controls) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous intravenous infusion of glucose-insulin-potassium (glucose objective 4.6–8<span class="elsevierStyleHsp" style=""></span>mmol/L); checks every 8<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">European Stroke Scale and Modified Rankin Scale at 90 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">With no significant reduction in mortality at 90 days (OR 1.14, 95% CI 0.86–1.51, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.37) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">THIS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2008 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ischemic stroke <12<span class="elsevierStyleHsp" style=""></span>h; all with diabetes mellitus; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>46 (31 interventions, 15 controls) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous intravenous insulin infusion (objective 5–7.2<span class="elsevierStyleHsp" style=""></span>mmol/L); checks every 1<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Difference in mean glucose between the 2 groups \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The glucose concentrations were significantly lower in the intervention group (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.001); 35% of hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">GRASP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2009 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ischemic stroke <24<span class="elsevierStyleHsp" style=""></span>h; n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>74 (24 interventions, 50 controls) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intravenous and subcutaneous insulin infusion (objective 3.9–11.1<span class="elsevierStyleHsp" style=""></span>mmol/L, nonstrict control) or continuous intravenous insulin infusion (objective 3.9–6.1<span class="elsevierStyleHsp" style=""></span>mmol/L, strict control); checks every 1–4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Glycemia levels within 24<span class="elsevierStyleHsp" style=""></span>h objective; hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Glycemia levels within objective in 90% of the nonstrict control, in 44% of the strict control group; 4% of hypoglycemia in the nonstrict control group and 30% in the strict control group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">Staszewski \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2011 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ischemic stroke <12<span class="elsevierStyleHsp" style=""></span>h; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>50 (26 interventions, 24 controls) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous intravenous insulin infusion (objective 4.5–7<span class="elsevierStyleHsp" style=""></span>mmol/L); check every 1<span class="elsevierStyleHsp" style=""></span>h, then every 4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The time within the target range \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">6.0 vs. 6.8<span class="elsevierStyleHsp" style=""></span>mmol/L (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.03); 8% fr hypoglycemia in the intervention group and 0% in the control group \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">INSULINFARC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">2012 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Ischemic stroke<span class="elsevierStyleHsp" style=""></span><6<span class="elsevierStyleHsp" style=""></span>h <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>180; 90 in each branch \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Continuous intravenous infusion of the actrapid insulin with hourly checks vs. subcutaneous insulin; glucose check every 4<span class="elsevierStyleHsp" style=""></span>h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Primary: proportion of patients with a mean capillary glucose level <7<span class="elsevierStyleHsp" style=""></span>mmol/L for 24<span class="elsevierStyleHsp" style=""></span>h Secondary: Infarction volume by magnetic resonance at 90 days, Rankin scale and mortality \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">The IIT regimen improved glucose control (95.4% vs. 67.4% <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.0001) but was associated with increased growth of the infarction \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001150.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Main studies with insulin for controlling glycemia in acute ischemic stroke.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AHA/ASA, American Heart Association/American Stroke Association; TIA, transient ischemic attack; SEN, Spanish Society of Neurology.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Recommendation \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Evidence Level \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">SEN</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Avoid the administration of serum glucose except when treating hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Level of evidence IIa; grade B recommendation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>It is recommended that glycemia levels<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>155<span class="elsevierStyleHsp" style=""></span>mg/dL be avoided \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Level of evidence IIa; grade B recommendation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top"><span class="elsevierStyleItalic">AHA/ASA</span></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>The evidence indicates that persistent hyperglycemia during the first 24<span class="elsevierStyleHsp" style=""></span>h in hospital after a stroke is associated with a poorer prognosis than with normal glycemia levels. Therefore, it is reasonable to treat hyperglycemia to achieve blood glucose levels within 140–180<span class="elsevierStyleHsp" style=""></span>mg/dL and closely monitor patients with acute ischemic stroke to prevent hypoglycemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Level of evidence IIa; grade C recommendation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Following a TIA or ischemic stroke, all patients should probably undergo a screening for diabetes by measuring plasma glucose levels under fasting conditions, HbA1c or by undergoing an oral glucose tolerance test. The selection of the test and when to perform it should be guided by clinical judgment, knowing that the acute disease can temporarily change the plasma glucose levels. In general, HbA1c can be more accurate than other detection tests immediately after the event \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Level of evidence IIa; grade C recommendation \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1001151.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Current recommendations for controlling hyperglycemia in acute ischemic stroke.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:42 [ 0 => array:3 [ "identificador" => "bib0215" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Instituto Nacional de Estadística. Defunciones según la causa de muerte. [accessed May 2015]. 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