P. Wouters

Insulin therapy protects the central and peripheral nervous system of intensive care patients

Objective: To investigate the effectiveness of maintaining blood glucose levels below 6.1 mmol/L with insulin as prevention of secondary injury to the central and peripheral nervous systems of intensive care patients. Methods: The authors studied the effect of intensive insulin therapy on critical illness polyneuropathy (CIPNP), assessed by weekly EMG screening, and its impact on mechanical ventilation dependency, as a prospectively planned subanalysis of a large randomized, controlled trial of 1,548 intensive care patients. In the 63 patients admitted with isolated brain injury, the authors studied the impact of insulin therapy on intracranial pressure, diabetes insipidus, seizures, and long-term rehabilitation at 6 and 12 months follow-up. Results: Intensive insulin therapy reduced ventilation dependency (p = 0.0007; Mantel–Cox log rank test) and the risk of CIPNP (p < 0.0001). The risk of CIPNP among the 405 long-stay (≥7 days in intensive care unit) patients was lowered by 49% (p < 0.0001). Of all metabolic and clinical effects of insulin therapy, and corrected for known risk factors, the level of glycemic control independently explained this benefit (OR for CIPNP 1.26 [1.09 to 1.46] per mmol blood glucose, p = 0.002). In turn, prevention of CIPNP explained the ability of intensive insulin therapy to reduce the risk of prolonged mechanical ventilation (OR 3.75 [1.49 to 9.39], p = 0.005). In isolated brain injury patients, intensive insulin therapy reduced mean (p = 0.003) and maximal (p < 0.0001) intracranial pressure while identical cerebral perfusion pressures were obtained with eightfold less vasopressors (p = 0.01). Seizures (p < 0.0001) and diabetes insipidus (p = 0.06) occurred less frequently. At 12 months follow-up, more brain-injured survivors in the intensive insulin group were able to care for most of their own needs (p = 0.05). Conclusions: Preventing even moderate hyperglycemia with insulin during intensive care protected the central and peripheral nervous systems, with clinical consequences such as shortening of intensive care dependency and possibly better long-term rehabilitation.

Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients

BACKGROUNDnMaintenance of normoglycaemia by use of insulin reduces morbidity and mortality of patients in surgical intensive care. Studies on mitochondrial function in critical illness or diabetes suggest that effects of intensive insulin therapy on mitochondrial integrity contribute to the clinical benefits.nnnMETHODSnEnzyme activities of the respiratory-chain complexes and oxidative-stress-sensitive glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were measured by spectrophotometry in 36 snap-frozen samples of liver and skeletal muscle obtained after death from patients who had been randomly assigned intensive (normoglycaemia) or conventional (hyperglycaemia) insulin therapy and who were similar in terms of admission diagnoses and causes of death. Mitochondrial ultrastructure was examined by electron microscopy in a random subgroup (n=20).nnnFINDINGSnIn the liver, hypertrophic mitochondria with an increased number of abnormal and irregular cristae and reduced matrix electron density were observed in seven of nine conventionally treated patients. Only one of 11 patients given intensive insulin treatment had these morphological abnormalities (p=0.005). The effect on ultrastructure was associated with higher activities of respiratory-chain complex I (median 1.53 [IQR 1.14-3.01] vs 0.81 [0.54-1.43] U/g liver; p=0.008) and complex IV (1.69 [1.40-1.97] vs 1.16 [0.97-1.40] U/g; p=0.008) in the intensive group than in the conventional group. There was no detectable difference in GAPDH activity. In skeletal muscle, mitochondrial ultrastructure and function were not affected by intensive insulin therapy.nnnINTERPRETATIONnStrict glycaemic control with intensive insulin therapy prevented or reversed ultrastructural and functional abnormalities of hepatocyte mitochondria. The lack of effect on skeletal-muscle mitochondria suggests a direct effect of glucose toxicity and glucose control, rather than of insulin, as the likely explanation.nnnRELEVANCE TO PRACTICEnMaintenance or restoration of mitochondrial function and cellular energetics is another therapeutic target, in addition to optimisation of cardiac output, systemic oxygen delivery, and regional blood flow, that might improve outcome for critically ill patients. Our findings could help to explain the mechanism underlying the reduction in mortality found when normoglycaemia was maintained with insulin, and further support use of intensive insulin therapy in this setting.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness

Backgroundu2002 Critical illness results in activation of the hypothalamic–pituitary–adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone‐binding domain exist, GRβ and GR‐P.

Effect of Tight Glucose Control with Insulin on the Thyroid Axis of Critically Ill Children and Its Relation with Outcome

CONTEXTnTight glucose control (TGC) to normal-for-age fasting blood glucose levels reduced morbidity and mortality in surgical adult and pediatric intensive care unit (ICU) patients. In adults, TGC did not affect the illness-induced alterations in thyroid hormones. With better feeding in children than in adult patients, we hypothesized that TGC in pediatric ICU patients reactivates the thyroid axis.nnnOBJECTIVEnThe aim of this study was to assess the impact of TGC on the thyroid axis in pediatric ICU patients and to investigate how these changes affect the TGC outcome benefit.nnnDESIGN AND PATIENTSnWe conducted a preplanned analysis of all patients not treated with thyroid hormone, dopamine, or corticosteroids who were included in a randomized controlled trial on TGC (n=700).nnnMAIN OUTCOME MEASURESnSerum TSH, T4, T3, and rT3 were measured upon admission and on ICU day 3 or the last ICU day for patients discharged earlier. Changes from baseline were compared for the TGC and usual care groups. The impact on the outcome benefit of TGC was assessed with multivariable Cox proportional hazard analysis, correcting for baseline risk factors.nnnRESULTSnTGC further lowered the T)/rT3 ratio (P=0.03), whereas TSH (P=0.09) and T4 (P=0.3) were unaltered. With TGC, the likelihood of earlier live discharge from the ICU was 19% higher at any time (hazard ratio, 1.190; 95% confidence interval, 1.010-1.407; P=0.03). This benefit was statistically explained by the further reduction of T3/rT3 with TGC because an increase in T3/rT3 was strongly associated with a lower likelihood for earlier live discharge (hazard ratio per unit increase, 0.863; 95% confidence interval, 0.806-0.927; P<0.0001).nnnCONCLUSIONSnTGC further accentuated the peripheral inactivation of thyroid hormone. This effect, mimicking a fasting response, statistically explained part of the clinical outcome benefit of TGC.

Ridotto metabolismo del cortisolo in corso di malattia critica

N Engl J Med 2013 March 19 as doi: 10.1056/NEJMoa1214969 La malattia critica, come lo stress fisico acuto intenso, è spesso associata a ipercortisolemia di entità proporzionale alla gravità della malattia. Tradizionalmente l’ipercortisolemia è attribuita all’attivazione dell’asse ipotalamo-ipofsi-surrene, con conseguente aumento della produzione di cortisolo ACTH-dipendente, tuttavia è stato riportato anche una ridotta concentrazione di ACTH nel corso di ipercortisolismo. In questo studio gli autori ipotizzano che l’ipercortisolismo sia dovuto ad un ridotto metabolismo del cortisolo con conseguente effetto di feedback negativo sull’ACTH. Per verificare questa ipotesi sono stati esaminati 158 soggetti ricoverati in terapia intensiva e 64 controlli sani; 5 aspetti del metabolismo del cortisolo sono stati considerati: le concentrazioni ematiche giornaliere di cortisolo e ACTH, la clearance plasmatica del cortisolo, il metabolismo e la sua produzione durante l’infusione di steroidi marcati, la clearance plasmatica di 100 mg di idrocortisone, le concentrazioni urinarie dei metaboliti del cortisolo e la concentrazione di mRNA e di proteine dei principali enzimi coinvolti nel metabolismo del cortisolo in biopsie del fegato e del tessuti adiposo in 44 soggetti deceduti. I risultati di questo studio evidenziavano concentrazioni plasmatiche di cortisolo libero più elevate nei pazienti critici rispetto ai soggetti di controllo, mentre le concentrazioni dell’ACTH erano ridotte. Vi era una riduzione del 50% della clearance del cortisolo dopo infusione di idrocortisone, che si correlava con una ridotta risposta allo stimolo corticotropinico; la riduzione del metabolismo del cortisolo valutato attraverso il rapporto tra gli steroidi urinari, la cinetica del cortisolo marcato e la valutazione delle biopsie epatiche si associava a una ridotta inattivazione dello stesso a livello del fegato e del rene, per una ridotta espressione della 5 alfa reduttasi e della 11 beta idrossisteroidodeidrogenasi tipo 2 Lo studio di Boonen e coll. dimostra che la genesi dell’ipercortisolemia nel paziente critico non dipende dall’attivazione dell’asse ipotalmo-ipofisi-surrene ma da un ridotto metabolismo periferico del cortisolo. Le citochine pro-infiammatorie, che raggiungono concentrazioni plasmatiche elevate nel paziente critico, possono essere considerate il principale fattore di riduzione della clearance metabolica del cortisolo e della sua sintesi surrenalica. Questo studio potrebbe contribuire a cambiare le conoscenze sulla risposta allo stress nel paziente critico e a modificarne la gestione terapeutica.

60 Intensive Insulin Therapy and Brief Hypoglycemia Do Not Increase Markers of Neurological Injury in Critically Ill Children

60 Intensive Insulin Therapy and Brief Hypoglycemia Do Not Increase Markers of Neurological Injury in Critically Ill Children