Frank Weekers

Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control.

ObjectivesMaintenance of normoglycemia with insulin reduces mortality and morbidity of critically ill patients. Here we report the factors determining insulin requirements and the impact of insulin dose vs. blood glucose control on the observed outcome benefits. DesignA prospective, randomized, controlled trial. SettingA 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital Patients and InterventionA total of 1,548 patients were randomly assigned to either strict normalization of blood glucose (80–110 mg/dL) with insulin infusion or the conventional approach, in which insulin is only given to maintain blood glucose levels at 180–200 mg/dL. Measurements and Main ResultsIt was feasible and safe to achieve and maintain blood glucose levels at <110 mg/dL by using a titration algorithm. Stepwise linear regression analysis identified body mass index, history of diabetes, reason for intensive care unit admission, at-admission hyperglycemia, caloric intake, and time in intensive care unit as independent determinants of insulin requirements, together explaining 36% of its variation. With nutritional intake increasing from a mean of 550 to 1600 calories/day during the first 7 days of intensive care, normoglycemia was reached within 24 hrs, with a mean daily insulin dose of 77 IU and maintained with 94 IU on day 7. Insulin requirements were highest and most variable during the first 6 hrs of intensive care (mean, 7 IU/hr; 10% of patients required >20 IU/hr). Between day 7 and 12, insulin requirements decreased by 40% on stable caloric intake. Brief, clinically harmless hypoglycemia occurred in 5.2% of intensive insulin-treated patients on median day 6 (2–14) vs. 0.8% of conventionally treated patients on day 11 (2–10). The outcome benefits of intensive insulin therapy were equally present regardless of whether patients received enteral feeding. Multivariate logistic regression analysis indicated that the lowered blood glucose level rather than the insulin dose was related to reduced mortality (p < .0001), critical illness polyneuropathy (p < .0001), bacteremia (p = .02), and inflammation (p = .0006) but not to prevention of acute renal failure, for which the insulin dose was an independent determinant (p = .03). As compared with normoglycemia, an intermediate blood glucose level (110–150 mg/dL) was associated with worse outcome. ConclusionNormoglycemia was safely reached within 24 hrs and maintained during intensive care by using insulin titration guidelines. Metabolic control, as reflected by normoglycemia, rather than the infused insulin dose per se, was related to the beneficial effects of intensive insulin therapy.

Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone-secretagogues†

Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF‐I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH‐secretagogues, GH‐releasing hormone (GHRH) and GH‐releasing peptide‐2 (GHRP‐2) in particular, on night‐time TSH and PRL secretion.

The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone

objective Central hyposomatotrophism, hypothyroidism and hypogonadism are present concomitantly in men with prolonged critical illness. This study evaluated the impact of combined treatment with GH‐releasing peptide‐2 (GHRP‐2), TRH and GnRH for 5 days compared with GHRP‐2 + TRH and with GHRP‐2 alone.

Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model

Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg·day (n = 9) or 160 μg/kg·day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-froze...

Propofol anesthesia does not inhibit stimulation of cortisol synthesis

Recent data suggest a negative effect of propofol anesthesia on cortisol secretion.The present study was designed to evaluate the effect of propofol anesthesia on the steroidogenic potential of the adrenal glands. The response of cortisol secretion to stimulation with an adrenocorticotropic hormone (ACTH) analog during intravenous anesthesia with propofol has not been reported before. The response of the secretion of cortisol, 11-deoxycortisol, and 17 alpha-hydroxyprogesterone to tetracosactide stimulation was compared in patients anesthetized with propofol-nitrous oxide (n = 10) or thiopental-isoflurane-nitrous oxide (n = 10) and in normal volunteers (n = 10). The response to tetracosactide was similar in all three groups. An adequate increase in cortisol plasma concentration (more than 7.25 micro gram/dL) was obtained in all subjects except one volunteer. The increase in the plasma concentration of the cortisol precursors was also similar. We were unable to detect any influence of propofol anesthesia on the synthesis of cortisol in response to tetracosactide stimulation. (Anesth Analg 1995;80:573-6)

Endocrine modifications and interventions during critical illness.

The ongoing hypermetabolic response in patients with prolonged critical illness leads to the loss of lean tissue mass. Since the cachexia of prolonged illness is usually associated with low concentrations of anabolic hormones, hormonal intervention has been thought to be beneficial. However, most interventions have been shown to be ineffective and their indiscriminate use even causes harm. Before considering endocrine intervention in these frail patients, a detailed understanding of the neuroendocrinology of the stress response is warranted. It is now clear that the acute phase and the later phase of critical illness behave differently from an endocrinological point of view. The acute stress response consists primarily of an actively-secreting pituitary in the presence of low circulating peripheral anabolic hormones, suggesting resistance of the peripheral tissues to the effects of anterior pituitary hormones. However, when the disease process becomes prolonged, there is a uniformly-reduced pulsatile secretion of anterior pituitary hormones with proportionally reduced concentrations of peripheral anabolic hormones. The origin of this suppressed pituitary secretion is located in the hypothalamus, as hypothalamic secretagogues can reactivate the anterior pituitary and restore pulsatile secretion. The reactivated pituitary secretion is accompanied by an increase in peripheral target hormones, indicating at least partial sensitivity of these tissues to anterior pituitary hormones in this chronic phase of illness. Thus, endocrine intervention with a combination of hypothalamic secretagogues that more completely reactivate the anterior pituitary could be a more physiological and effective strategy for inducing anabolism in patients with prolonged critical illness.

One Fourth of Unplanned Transfers to a Higher Level of Care Are Associated With a Highly Preventable Adverse Event: A Patient Record Review in Six Belgian Hospitals

Objective: The objectives of this study are to determine the prevalence and preventability of adverse events requiring an unplanned higher level of care, defined as an unplanned transfer to the ICU or an in-hospital medical emergency team intervention, and to assess the type and the level of harm of each adverse event. Design: A three-stage retrospective review process of screening, record review, and consensus judgment was performed. Setting: Six Belgian acute hospitals. Patients: During a 6-month period, all patients with an unplanned need for a higher level of care were selected. Interventions: The records 6-month period, the records of all patients with an unplanned need for a higher level of care were assessed by a trained clinical team consisting of a research nurse, a physician, and a clinical pharmacist. Measurements and Main Results: Adverse events were found in 465 of the 830 reviewed patient records (56%). Of these, 215 (46%) were highly preventable. The overall incidence rate of patients being transferred to a higher level of care involving an adverse event was 117.6 (95% CI, 106.9–128.3) per 100,000 patient days at risk, of which 54.4 (95% CI, 47.15–61.65) per 100,000 patient days at risk involving a highly preventable adverse event. This means that 25.9% of all unplanned transfers to a higher level of care were associated with a highly preventable adverse event. The adverse events were mainly associated with drug therapy (25.6%), surgery (23.7%), diagnosis (12.4%), and system issues (12.4%). The level of harm varied from temporary harm (55.7%) to long-term or permanent impairment (19.1%) and death (25.2%). Although the direct causality is often hard to prove, it is reasonable to consider these adverse events as a contributing factor. Conclusion: Adverse events were found in 56% of the reviewed records, of which almost half were considered highly preventable. This means that one fourth of all unplanned transfers to a higher level of care were associated with a highly preventable adverse event.