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Background: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known.Methods: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]).Results: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care.Conclusions: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit. [ABSTRACT FROM AUTHOR]

Purpose: Mechanical bowel preparation is common practice in elective colon surgery. In recent literature the value of this procedure is under discussion. To verify the value of mechanical bowel preparation in elective open colon surgery, a randomized clinical trial was conducted., Methods: During a prospective, multicenter, randomized study, 250 patients undergoing elective open colon surgery were randomized between receiving mechanical bowel preparation with polyethylene glycol (PEG group, 125 patients) and having a normal meal preoperatively (normal meal preoperatively group, 125 patients). Outcome parameters were wound infection with bacterial results of intraoperative swabs and anastomotic leak., Results: In the polyethylene glycol group there were a total of nine wound infections (7.2 percent) and seven anastomotic leaks (5.6 percent) compared with seven wound infections (5.6 percent) (P = 0.61) and six anastomotic leaks (4.8 percent) (P = 0.78) in the normal meal preoperatively group. Bacterial results showed 52 percent sterile subcutis swabs in the PEG group and 63 percent sterile subcutis swabs in the normal meal preoperatively group (P = 0.11)., Conclusion: In the present study we could not detect a difference in outcome parameters between patients receiving mechanical bowel preparation in elective open colon surgery and patients without preoperative treatment of the bowel. The present study, although underpowered, did not show a difference in the primary outcome of bacterial wound cultures between patients receiving preoperative mechanical bowel preparation and patients receiving no preoperative bowel treatment. We conclude that there may be no need to continue the use of mechanical bowel preparation in elective open colon surgery.

Background: In contrast with kidneys, transplantation of livers originating from non-heart-beating donors remains rare, mainly because warm ischemia causes a higher rate of potentially lethal primary graft nonfunction. Little is known on the tolerance of liver grafts to warm ischemia. No techniques are available to assess the viability of ischemic livers before implantation. Therefore, experimental models are needed to address these questions before non-heart-beating liver transplantation can be more widely applied. This study aims to develop a reproducible large animal model of liver transplantation using non-heart-beating donors and, in this model, to define the tolerance of the liver to warm ischemia., Methods: Pigs weighing 25to 30 kg are used. In donors, cardiac arrest is caused by ventricular fibrillation. After increasing lengths of warm ischemia (0, 15, 30, 45, and 60 min), the liver is flushed in situ with 4 degrees C histidine tryptophan ketoglutarate preservation solution and procured. The liver is transplanted after a 4-hour cold storage period., Results: Control livers (no warm ischemia) and livers exposed to 15 minutes of warm ischemia function normally after transplantation, whereas all livers submitted to 60 minutes of warm ischemia display primary nonfunction and cause recipient death. Graft function and survival are occasionally observed after 30 and 45 minutes of warm ischemia., Conclusions: A reproducible model of non-heart-beating liver transplantation is described. We found that the liver tolerates 15 minutes of warm ischemia. This preclinical model is a valid tool to develop techniques to predict the quality of ischemic livers before implantation and to design interventional strategies to improve the tolerance of the liver to warm ischemia.

Objective: To find a subset of patients with suspected central venous catheter (CVC)-related infection (CRI) in whom CVC removal is not needed., Design: Randomized controlled trial., Setting: Thirty-three-bed ICU., Patients and Participants: One hundred and forty four patients with suspected CRI in which a change of CVCs was planned were evaluated for inclusion., Interventions: Hemodynamically stable patients without proven bacteremia, no insertion site infection, and no intravascular foreign body were randomized to a standard-of-care group (SOC, all CVCs were changed as planned) or a watchful waiting group (WW, CVCs changed when bacteremia was subsequently confirmed or hemodynamic instability occurred)., Measurement and Results: Study groups were compared for incidence of CVC-related bloodstream infection (CR-BSI), resolution of fever, C-reactive protein, SOFA score, duration of ICU stay, and mortality. Of 144 patients with suspected CRI, 80 patients met exclusion criteria. Sixty-four were randomized. Forty-seven of 80 excluded patients were shown to be bacteremic, 20 (25%) of whom had a CR-BSI. Five of 64 (8%) included patients had a CR-BSI during their subsequent ICU stay (two in SOC and three in WW group). All 38 CVCs were changed in the SOC group versus 16 of 42 in the WW group (62% reduction, P<0.01). Resolution of fever, C-reactive protein, SOFA score, duration of ICU stay, and ICU mortality did not differ between SOC and WW group ( P>0.1 for all)., Conclusions: The use of a simple clinical algorithm permits a substantial decrease in the number of unnecessarily removed CVCs without increased morbidity.

Mortality of generalized postoperative peritonitis remains high at 22% to 55%. The aim of the present study was to identify prognostic factors by means of univariate and multivariate analysis in a consecutive series of 96 patients. Mortality was 30%. Inability to clear the abdominal infection or to control the septic source, older age, and unconsciousness were significant factors related to mortality in the multivariate analysis. Failure to control the peritoneal infection (15%) was always fatal and correlated with failed septic source control, high Acute Physiology and Chronic Health Evaluation (APACHE) II score, and male gender. Failure to control the septic source (8%) also was always fatal and correlated with high APACHE II score and therapeutic delay. In patients with immediate source control, residual peritonitis occurred in 9% after purulent or biliary peritonitis and in 41% after fecal peritonitis ( p = 0.002). In patients without immediate control of the septic source, delayed control was still achieved in 100% after a planned relaparotomy (PR) strategy versus 43% after an on-demand relaparotomy (ODR) strategy ( p = 0.018). In the same patients, mortality was 0% in the PR group versus 64% in the ODR group ( p = 0.007). Early relaparotomy is related to improved septic source control. After relaparotomy for generalized postoperative peritonitis, a PR strategy is indicated whenever source control is uncertain. It also might decrease mortality in fecal peritonitis. An ODR approach is adequate for purulent and biliary peritonitis with safe septic source control.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Prolonged critical illness is characterized by protein hypercatabolism and preservation of fat depots, associated with blunted GH secretion, elevated serum cortisol levels, and low insulin-like growth factor I (IGF-I) concentrations. In this condition, GH is readily released in response to a bolus of GHRH and GH-releasing peptide-2 (GHRP-2) and, paradoxically, to TRH. We further explored the altered somatotropic axis and cortisol secretion in critical illness by examining the effects of continuous GHRH and/or GHRP-2 infusion. Twenty-six critically ill adults (mean age +/- SEM, 63 +/- 2 yr) were studied during 2 consecutive nights (2100-0600 h). According to a weighed randomization, they received one of four combinations of infusions within a randomized cross-over design for each combination: placebo (one night) and GHRP-2 (the other night; n = 10), placebo and GHRH (n = 4), GHRH and GHRP-2 (n = 6), and GHRP-2 and GHRH plus GHRP-2 (n = 6). The peptide infusions (duration, 21 h) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h. Serum concentrations of GH were determined every 20 min, cortisol every hour, and IGF-I at 2100 and 0600 h on each study night. The placebo profiles showed pulsatile GH secretion with low secretory burst amplitude [0.062 +/- 0.008 microgram/L distribution volume (Lv)/min], high burst frequency (6.6 +/- 0.4 events/9 h), and detectable basal secretion (0.041 +/- 0.009 microgram/L/min) in the face of low serum IGF-I (106 +/- 11 micrograms/L). IGF-I correlated positively and significantly with the basal component, the pulsatile component, and the total amount of nightly GH secretion. GHRH elicited a 2- to 3-fold increase in the mean GH concentration (P = 0.006), the GH secretory burst amplitude (P = 0.007), and basal GH secretion (P = 0.03). GHRP-2 provoked a 4- to 6-fold increase in the mean GH concentration (P < 0.0001), the GH secretory burst amplitude (P = 0.002), and basal GH secretion (P = 0.0007), which were associated with a 61 +/- 13% increase in serum IGF-I within 24 h (P = 0.02). Compared to GHRP-2 alone, GHRH plus GHRP-2 elicited a further 2-fold increase in the mean GH concentration (P = 0.04) and GH basal secretion (P = 0.02), and an additional 40 +/- 6% rise in serum IGF-I (P = 0.04). GHRH and GHRP-2 infusion did not alter elevated cortisol levels. In critically ill adults, low serum IGF-I levels were positively correlated with diminished pulsatile and increased basal GH secretion. Both basal and pulsatile GH secretion were moderately increased by continuous infusion of GHRH, substantially increased by GHRP-2, and strikingly increased by GHRH plus GHRP-2. GHRP-2 alone or combined with GHRH elicited a robust rise in circulating IGF-I levels within 24 h without altering serum cortisol levels. These findings open perspectives for GH secretagogues as potential antagonists of the catabolic state in critical care medicine.

Objective: To evaluate the efficacy of two regimens of selective decontamination of the digestive tract in mechanically ventilated patients., Design: Prospective, randomized, concurrent trial., Setting: Multidisciplinary intensive care unit (ICU) in a 1,800-bed university hospital., Patients: Consecutive patients (n = 660) who were likely to require mechanical ventilation for at least 48 hrs were randomized to one of three groups: conventional antibiotic regimen (control group A); oral and enteral ofloxacin-amphotericin B (group B); and oral and enteral polymyxin E-tobramycin-amphotericin B (group C). Both treatment groups received systemic antibiotics for 4 days (ofloxacin in group B and cefotaxime in group C)., Interventions: Patients were randomized to receive standard treatment (control group A, n = 220), selective decontamination regimen B (group B, n = 220), and selective decontamination regimen C (group C, n = 220). After early deaths and exclusions from the study, 185 controls (group A) and 193 (group B)/200 (group C) selective decontamination regimen patients were available for analysis., Measurements and Main Results: Measurements included colonization and primary/secondary infection rate, ICU mortality rate, emergence of antibiotic resistance, length of ICU stay, and antimicrobial agent costs. The study duration was 19 months. The patient groups were fully comparable for age, diagnostic category, and severity of illness. One third of patients in each group suffered a nosocomial infection at the time of admission. There was a significant difference between treatment group B and control group A in the number of infected patients (odds ratio of 0.42, 95% confidence interval of 0.27 to 0.64), secondary lower respiratory tract infection (odds ratio of 0.47, 95% confidence interval of 0.26 to 0.82), and urinary tract infection (odds ratio of 0.47, 95% confidence interval of 0.27 to 0.81). Significantly more Gram-positive bacteremias occurred in treatment group C vs. group A (odds ratio of 1.22, 95% confidence interval 0.72 to 2.08). Infection at the time of admission proved to be the most significant risk factor for subsequent infection in control and both treatment groups. ICU mortality rate was almost identical (group A 16.8%, group B 17.6%, and group C 15.5%) and was not significantly related to primary or secondary infection. Increased antimicrobial resistance was recorded in both treatment groups: tobramycin-resistant enterobacteriaceae (group C 48% vs. group A 14%, p < .01), ofloxacin-resistant enterobacteriaceae (group B 50% vs. group A 11%, p < .02), ofloxacin-resistant nonfermenters (group B 81% vs. group A 52%, p < .02), and methicillin-resistant Staphylococcus aureus (group C 83% vs. group A 55%, p < .05). Antimicrobial agent costs were comparable in control and group C patients; one third less was spent for group B patients., Conclusions: In cases of high colonization and infection rates at the time of ICU admission, the preventive benefit of selective decontamination is highly debatable. Emergence of multiple antibiotic-resistant microorganisms creates a clinical problem and a definite change in the ecology of environmental, colonizing, and infecting bacteria. The selection of multiple antibiotic-resistant Gram-positive cocci is particularly hazardous. No beneficial effect on survival is observed. Moreover, selective decontamination adds substantially to the cost of ICU care.

Objective: Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration., Patients and Design: Critically ill adults (n = 40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n = 10), GHRH and GHRP-2 (n = 10), GHRP-2 and GHRH+GHRP-2 (n = 10), GHRH+GHRP-2 and GHRH+GHRP-2 + TRH (n = 10). The GHRH and GHRP-2 doses were 1 microgram/kg and the TRH dose was 200 micrograms. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection., Measurements: Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA., Results: Critically ill patients presented a striking GH response to GHRP-2 (mean +/- SEM peak GH 51 +/- 9 micrograms/l in older patients and 102 +/- 26 micrograms/l in younger patients; P = 0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P = 0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P = 0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P = 0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response > ninefold (P = 0.005), elicited a 60% rise in serum T3 (P = 0.01) and an 18% increase in T4 (P = 0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P = 0.007). GHRP-2 increased basal serum cortisol levels (531 +/- 29 nmol/l) by 35% (P = 0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P = 0.05)., Conclusions: The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.

Objective: The aim of this study was to examine the effect of dopamine infusion on the thyrotropin (TSH), thyroid hormone, prolactin, and growth hormone responses to thyrotropin-releasing hormone (TRH) in critically ill patients., Design: Prospective, randomized, controlled, open-labeled clinical study., Setting: The intensive care unit, University Hospital Gasthuisberg, Leuven, over a 1-month period., Patients and Interventions: In 15 critically ill patients receiving dopamine treatment (5 micrograms/kg/min) for a mean of 43.3 +/- 1.2 (SEM) hrs after trauma or cardiac surgery, we studied the TSH, thyroid hormone, prolactin, and growth hormone responses to the administration of two consecutive intravenous TRH boluses of 200 micrograms, with a 6-hr interval. The dopamine infusion was continued in the control group and discontinued in the study group. Serum concentrations of TSH, prolactin, and growth hormone were measured before and 20, 40, 60, and 120 mins after TRH administration. Serum concentrations of thyroxine (T4), triiodothyronine (T3), reverse T3, and thyroid hormone binding globulin were determined before and 120 mins after each TRH injection., Measurements and Main Results: There was a > 100-fold interindividual variation in the baseline TSH concentration and in the TSH peak value after TRH administration. Two consecutive doses of TRH evoked a mean 16% increase in serum T4 concentration (p = .003) and a mean 47% increase in T3 (p = .001), whereas serum reverse T3 and thyroid hormone binding globulin values remain unaltered. Each of the TRH boluses increased serum growth hormone concentrations in the continued dopamine and discontinued dopamine groups, by a median of 60% (p = .001) and 68% (p = .001), respectively. Three hours after dopamine withdrawal, there was a three-fold increase of the peak TSH response (p = .001), a higher T3 response (p = .01), and a ten-fold increase of the peak prolactin value (p = .001) in response to TRH administration., Conclusions: The TSH response to TRH administration in critical illness presents a striking interindividual variation and dopamine dependent. Repeated TRH administration results in a repetitive increase of TSH, prolactin, growth hormone, T4, and T3, without increasing reverse T3. These observations point toward a potential for TRH as a strategy for reversing the euthyroid sick syndrome, growth hormone deficiency, and immune dysfunction associated with critical illness.

Objective: As part of a study on the effect of dopamine therapy on pituitary dependent hormone secretion in critical illness, we documented the impact of this inotropic and vasoactive catecholamine on the serum concentrations of dehydroepiandrosterone sulphate (DHEAS). Concomitantly, serum levels of PRL and cortisol were determined., Patients and Design: In a prospective, randomized, controlled, open-labelled clinical study, 20 critically ill, adult polytrauma patients receiving dopamine treatment (5 micrograms/kg/mi i.v. for a median 109 hours (range (21-296 hours)), were studied to evaluate the effect of dopamine withdrawal on serum concentrations of DHEAS, PRL and cortisol. The median age of the studied patients was 37 years (range 18-83 years)., Measurements: Serum DHEAS and cortisol concentrations were measured by RIA and PRL by IRMA. The assessed serum samples were obtained at 0300 h on each of two consecutive study nights., Results: Withdrawal of dopamine infusion was found to elicit a median 25% increase of serum DHEAS concentrations within 24 hours whereas no significant change in DHEAS levels was observed when dopamine infusion was continued throughout both study nights (P = 0.01 continued vs interrupted dopamine). Prolactin levels were undetectable as long as dopamine was infused, and increased to a median of 317 IU/l after 24 hours of dopamine withdrawal (P = 0.0007). Elevated serum cortisol levels remained comparable with continued and interrupted dopamine infusion., Conclusions: Dopamine infusion appears to suppress serum DHEAS concentrations in critically ill patients without affecting their elevated serum cortisol levels, suggesting a differential regulation of DHEAS and cortisol metabolism in critical illness. The lowering effect of dopamine on DHEAS levels could be linked to the concomitant suppression of circulating PRL. The simultaneous suppression of circulating PRL and DHEAS by dopamine infusion may be an iatrogenic factor maintaining or aggravating the anergic state of prolonged severe illness.

The new water-soluble benzodiazepine midazolam was compared in a randomized study to diazepam for postoperative sedation in fifty patients following aortocoronary bypass surgery with a sufentanil-anesthesia. Midazolam and diazepam were administered intravenously in repeated doses in conjunction with an opioid infusion (piritramide) from the end of surgery during a twelve-hour study period, patients being artificially ventilated. Midazolam scored better than diazepam for quality of sedation and cardiovascular stability during the period of mechanical ventilation and for respiration during the weaning period and after extubation, although no difference was found in weaning time from artificial ventilation and time of extubation. Hemodynamic tolerance for both drugs was good. The administration of a loading dose of midazolam 5 mg caused a slight, transient decrease in mean arterial pressure. Midazolam appeared to be a more effective sedative agent than diazepam for short-term administration during mechanical ventilation. No evidence of cumulation and prolonged recovery was seen.