The study was conducted on patients admitted to the Department of Intensive Internal Medicine, General Hospital Celje, Slovenia, between January 2005 and December 2006. We included those critically ill patients who met the criteria for severe sepsis with acute respiratory failure requiring artificial ventilation. The following criteria for severe sepsis were considered: body temperature above 38°C or below 36°C, heart rate over 90 bpm, respiratory rate over 20 breaths/min or partial pressure of arterial carbon dioxide below 32 mmHg, leukocyte count over 12.0 × 109/l or below 4.0 × 109/l [8]. Those patients were included who met at least two criteria of sepsis. No diabetic patients were included in the study. Patients requiring artificial ventilation due to primary failure of respiratory muscles and those who required artificial ventilation due to brain injury were also excluded. Prior to inclusion, the patients' legal representatives signed written consent for participation in the study. The patients were randomized into two groups as regards the regulation of blood glucose: intensive (Group 1) and conventional (Group 2). In the conventional protocol the blood glucose concentration was maintained within the range of 7.0 to 11.0 mmol/l, while in the intensive protocol the concentration was maintained within the range of 4.4 to 6.1 mmol/l. The lower level (7 mmol/l) in patients receiving the conventional protocol was selected as per the proposal by the supervisory committee, because the recommendations at that time favoured blood glucose levels less than 8.3 mmol/l [9]. In a 50 ml syringe, 50 IU of human insulin for intravenous administration was diluted in a 0.9% solution of sodium chloride. The amount of infusion was adjusted according to the values of blood glucose concentrations in conformity with a previously published protocol [10]. The blood glucose concentration was determined hourly using the hexokinase method at the beginning of insulin treatment, and every two hours thereafter, except when the dose of insulin was adjusted; in this case, the next measurement was taken after one hour. The treatment was initiated within 48 hours of the start of artificial ventilation. Up to that point, the blood glucose concentrations were maintained in the 8.8 to 11.0 mmol/l range by means of subcutaneous administration of rapid-acting insulin or the infusion described above.
Hypoglycemia, a possible adverse event occurring during insulin treatment, was defined as a decrease in blood glucose concentration to values below 2.2 mmol/l, and was suspected in cases where the patient suffered sudden perspiration, convulsions, and change in heart rate or blood pressure. In these cases, administration of insulin was interrupted and blood was taken to determine the glucose levels. In addition, we performed a bedside test to determine the glucose values. If the blood glucose values were found to be below 2.2 mmol/l, we terminated the insulin infusion and the patient was intravenously administered 25 g of glucose in the form of a 50% solution.
All patients were continuously subjected to hemodynamic monitoring with the following measurements: continuous monitoring of the electrocardiography curve, and invasive measurement of arterial and central venous pressure. Cardiac output was continuously monitored by means of the thermodilution method (Edwards Lifesciences, Vigilance, Irvine, CA, USA).
Any additional monitoring was introduced by the principal physician, depending on the patient's clinical status.
The severity of the patients' clinical status was assessed by means of the Acute Physiology and Chronic Health Evaluation (APACHE) II score system routinely used for all patients treated at the department [11, 12]. All patients were artificially ventilated with a Siemens Servo ventilator 300 set (Danvers, MA, USA) to pressure regulated volume control with a tidal volume of 5 to 7 ml/kg.
The patients were given food using a nasogastric tube as soon as possible, mostly after the initial 12-hour volume resuscitation. The food was administered between 6 a.m. and 10 p.m. During the overnight break in feeding the insulin dose was halved regardless of the insulin treatment protocol. Patients who did not tolerate enteral feeding received food in the form of a parenteral infusion of nutrients, and the insulin dose was adjusted based on the blood glucose levels.
The study was approved by the State Ethics Committee.
Strain-gauge plethysmography
Measurements of forearm flow were performed by means of a plethysmograph (model EC5R, D.E. Hokanson, Inc., Bellevue, WA, USA). A detailed test procedure is described elsewhere [13, 14]. Briefly, the patient was in a supine position with the upper body lifted by approximately 15°C. The forearm was positioned in the level of the right atrium (at 3/5 chest height). A 10 cm wide cuff was placed on the forearm and connected to the rapid cuff inflator. A mercury-filled clamp with a circumference 1.5 to 2 cm smaller than the forearm circumference was placed on the widest part of the forearm. A second 8 cm wide cuff was placed just above the wrist in order to block arterial inflow to the thermoregulatory area, in our case the hand. The upper arm cuff pressure was preset to 50 mmHg. After 10 seconds of inflation the cuff was deflated for five seconds. Prior to the measurement, the wrist cuff was inflated to the value 40 mmHg above the systolic pressure for the duration of a single measurement (approximately one minute). The plethysmographic curve was recorded and measurement was repeated every 10 minutes, with each individual measurement lasting one hour.
The instantaneous arterial flow was calculated manually by analysing the plethysmographic recording.
The values of the instantaneous arterial flow were expressed as ml/100 ml of tissue/min. To estimate the total forearm flow, the area under the 60-minute arterial flow curve was calculated. All arterial flow measurements were taken at the beginning of the study (t0), after 2 hours (t1), after 24 hours (t2), and after 72 hours (t3) between 8 a.m. and 9 a.m., with the exception of insulin infusion measurements, which were taken between 11 a.m. and 12 p.m.
Laboratory tests
To determine blood glucose levels, blood was taken from an arterial catheter for hemodynamic monitoring every hour at the beginning of the study, and every two hours thereafter if the insulin infusion was not changed. Exceptionally, if hypoglycemia was suspected, a bedside test was performed to determine the glucose level from capillary blood; the test was always verified by collecting arterial blood. Serum glucose was determined on the Roche Modular (Hitachi Ltd, Tokyo, Japan) apparatus using the hexokinase method.
Statistical model
The study was designed as a prospective, randomized, parallel study. Student's t-test of independent samples was used for comparisons between the two groups. Blood glucose concentrations showed a deviation from normal distribution; in this case, consequently, the comparisons between the groups were made using Mann-Whitney test. To compare categorical values, either the chi-squared test or Fisher's exact test was used, according to appropriateness. To calculate statistical differences in flows between the two groups of patients, the area under the flow curve during the one-hour measurement was considered as an individual piece of data. The area was calculated using the trapezoid rule [15].
The sample size was estimated at 30 patients based on findings from previously published data and on the basis of results from our own pilot study [16]. The data are expressed here as mean value ± standard deviation or, in the case of abnormal distribution, as the median, interquartile range or range between the minimum and maximum value. Linear regression analysis and the Pearson correlation coefficient were used to determine the levels of correlation. The value P < 0.05 was deemed as a statistically significant difference. Statistical calculations were carried out using the programme SPSS for Windows 10.0 (Chicago, Il, USA).
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