Dean R. Chittock

Intensive versus conventional glucose control in critically ill patients

BACKGROUND The optimal target range for blood glucose in critically ill patients remains unclear. METHODS Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization. RESULTS Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39). CONCLUSIONS In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987.)

Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data

Background: Hyperglycemia is associated with increased mortality in critically ill patients. Randomized trials of intensive insulin therapy have reported inconsistent effects on mortality and increased rates of severe hypoglycemia. We conducted a meta-analysis to update the totality of evidence regarding the influence of intensive insulin therapy compared with conventional insulin therapy on mortality and severe hypoglycemia in the intensive care unit (ICU). Methods: We conducted searches of electronic databases, abstracts from scientific conferences and bibliographies of relevant articles. We included published randomized controlled trials conducted in the ICU that directly compared intensive insulin therapy with conventional glucose management and that documented mortality. We included in our meta-analysis the data from the recent NICE-SUGAR (Normoglycemia in Intensive Care Evaluation — Survival Using Glucose Algorithm Regulation) study. Results: We included 26 trials involving a total of 13 567 patients in our meta-analysis. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% confidence interval [CI] 0.83–1.04). Among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5–8.0). The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63, 95% CI 0.44–0.91); patients in the other ICU settings did not (medical ICU: RR 1.0, 95% CI 0.78–1.28; mixed ICU: RR 0.99, 95% CI 0.86–1.12). The different targets of intensive insulin therapy (glucose level ≤ 6.1 mmol/L v. ≤ 8.3 mmol/L) did not influence either mortality or risk of hypoglycemia. Interpretation: Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients. However, this therapy may be beneficial to patients admitted to a surgical ICU.

Beneficial Effects of Short-term Vasopressin Infusion during Severe Septic Shock

Background Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion. Methods Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured. Results Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 &mgr;g/min to a blinded infusion of 17.0 &mgr;g/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 &mgr;g/min to 5.3 &mgr;g/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h;P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group. Conclusions The authors conclude that short-term vasopressin infusion spared conventional vasopressor use and improved some measures of renal function in patients with severe septic shock.

Measuring quality of sedation in adult mechanically ventilated critically ill patients: the Vancouver Interaction and Calmness Scale

There are no reliable, valid, and responsive scales to measure the quality of sedation in adult critically ill patients. Our objective was to develop a summated rating scale with these properties and to define the minimal clinically important difference (MCID). We developed and tested the scale in an 18-bed medical-surgical intensive care unit (ICU) (12-bed acute and 6-bed subacute unit). Following identification of relevant domains and item derivation, 116 observations were made on 38 patients; psychometric properties and interrater reliability were assessed to allow item reduction. The final scale consisted of two five-item subscales quantifying calmness and interaction along a continuum from 5 to 30 points. Interrater reliability was 0.89 and 0.90; internal consistency was 0. 95 for both subscales. To test construct validity, MCID, and responsiveness 302 observations were made on 54 patients. Construct validity: calmness score vs. need for further intervention to make the patient calm (R = -0.82, P < 0.001); interaction score discriminated between acute vs. subacute units, mean scores 15.28 +/- 8.26 vs. 23.54 +/- 7.42, mean difference 8.27 (95% CI - 10.32 to -6.22); MCID - 2.2 and 2.5 for the calmness and interaction subscales; Guyatts responsiveness statistics - 1.4 and 2.3. The Vancouver Interaction and Calmness Scale (VICS) is reliable, valid, and responsive.

Severity of illness and risk of death associated with pulmonary artery catheter use

ObjectiveTo examine the association between the use of the pulmonary artery catheter and mortality rate in critically ill patients with a higher vs. a lower severity of illness. DesignObservational cohort study. SettingA tertiary care university teaching hospital from March 1988 to March 1998. PatientsA total of 7,310 critically ill adult patients. InterventionsNone. Measurements and Main ResultsThe main outcome measure was hospital mortality rate, controlled by multivariable logistic regression within four patient groups based on severity of illness. Cutoffs for severity of illness were chosen based on Acute Physiology and Chronic Health Evaluation (APACHE) II score 25th percentiles. Logistic regression analysis demonstrated no increased risk of death associated with exposure to the pulmonary artery catheter in the population as a whole. The associated odds ratio of hospital death for the entire cohort was 1.05 (95% confidence interval, 0.92–1.21). Subgroup analysis of severity of illness revealed the highest risk of death to be associated with the lowest APACHE II score quartile vs. a decreased associated mortality rate with the highest APACHE II score quartile after adjustment with multivariable logistic regression (APACHE II <18: odds ratio, 2.47, 95% confidence interval, 1.27–4.81; APACHE II 18–24: odds ratio, 1.64, 95% confidence interval, 1.24–2.17; APACHE II 25–31: odds ratio, 1.00, 95% confidence interval, 0.80–1.24; APACHE II >31: odds ratio, 0.80, 95% confidence interval, 0.64–1.00). ConclusionsThe use of the pulmonary artery catheter may decrease mortality rate in the most severely ill while increasing it in a population with a lower severity of illness. These findings underscore the necessity of examining the effect of severity of illness in future randomized controlled trials.

Association of hemoglobin concentration and mortality in critically ill patients with severe traumatic brain injury

IntroductionThe critical care management of traumatic brain injury focuses on preventing secondary ischemic injury. Cerebral oxygen delivery is dependent upon the cerebral perfusion pressure and the oxygen content of blood, which is principally determined by hemoglobin. Despite its importance to the cerebral oxygen delivery, the precise hemoglobin concentration to provide adequate oxygen delivery to injured neuronal tissue in TBI patients is controversial with limited evidence to provide transfusion thresholds.MethodsWe conducted a retrospective cohort study of severe TBI patients, investigating the association between mean 7-day hemoglobin concentration and hospital mortality. Demographic, physiologic, intensive care interventions, clinical outcomes and daily hemoglobin concentrations were recorded for all patients. Patients were all cared for at a tertiary, level 1 trauma center in a mixed medical and surgical intensive unit. Patients were divided into quartiles based on their mean 7-day hemoglobin concentration: < 90 g/L, 90 - 99 g/L, 100 - 109 g/L and > 110 g/L. Multivariable log-binomial regression was used to model the association between mean daily hemoglobin concentration and hospital mortality.ResultsTwo hundred seventy-three patients with traumatic brain injury were identified and 169 were included in the analysis based on inclusion/exclusion criteria. Of these, 77% of the patients were male, with a mean age of 38 (SD 17) years and a median best GCS of 6 (IQR 5 - 7). One hundred fifteen patients (68%) received a red blood cell (RBC) transfusion. In RBCs administered in the ICU, the median pre-transfusion hemoglobin was 79 g/L (IQR 73 - 85). Thirty-seven patients (22%) died in hospital. Multivariable analysis revealed that mean 7-day hemoglobin concentration < 90 g/L was independently associated with an increased risk of hospital mortality (RR 3.1, 95% CI 1.5 - 6.3, p = 0.03). Other variables associated with increased mortality on multivariable regression were insertion of external ventricular drain, age and decreased GCS. Red blood cell transfusion was not associated with mortality following multivariable adjustment.ConclusionsA mean 7-day hemoglobin concentration of < 90g/L is associated with increased hospital mortality in patients with severe traumatic brain injury.

Interpretation of Transbronchial Lung Biopsies from Lung Transplant Recipients:Inter- and Intraobserver Agreement

BACKGROUND Transbronchial lung biopsy results are crucial for the management of lung transplant recipients. Little information is available regarding the reliability and reproducibility of the interpretation of transbronchial lung biopsies. OBJECTIVE To examine the inter-reader variability between two lung pathologists with expertise in lung transplantation. METHODS Fifty-nine transbronchial lung biopsy specimens were randomly selected. Active infection had been excluded in all cases. The original interpretations (as per the Lung Rejection Study Group) for acute rejection grade included 19 biopsies scored as A0 (none), 14 scored as A1 (minimal), 12 as A2 (mild), 11 as A3 (moderate) and three as A4 (severe). The pathologists worked independently without clinical information or knowledge of the original interpretation. The specimens were graded using the Lung Rejection Study Group criteria for acute rejection (grades A0 to A4), airway inflammation (grades B0 to B4) and bronchiolitis obliterans (C0 absent and C1 present). Between-reader agreement for each category was analyzed using a Kappa statistic. RESULTS Because many transplant specialists initiate augmented immunosuppression with biopsy grades of A2 or higher, results for each reader were dichotomized as A0/A1 versus A2/A3/A4. Using this dichotomy, there was only moderate agreement (kappa 0.470, P < 0.001) between readers. For categories B and C, the results were dichotomized for the absence or presence of airway inflammation and bronchiolitis obliterans, respectively. The level of agreement between readers was fair for category B (kappa 0.333, P = 0.014) and poor for category C (kappa 0.166, P = 0.108). The intrareader agreement for acute rejection was substantial (kappa 0.795, P = 0.0001; kappa 0.676, P = 0.0001). CONCLUSIONS Because the agreement between expert pathologists is only modest, optimum clinical decision-making requires that transbronchial lung biopsy results be used in an integrated clinical context.

Stress test and gastric-arterial PCO2 measurement improve prediction of successful extubation.

Objective Correct early prediction of successful extubation decreases morbidity and mortality. The use of single time point measurements and surrogate markers of true extubation success limits weaning studies. Our aim was to determine whether a “stress test” improves prediction of extubation outcome and to determine the most predictive variables. Design Observational study. Setting Intensive care unit of a teaching hospital. Patients A convenience sample of 68 patients judged to be ready for extubation. Interventions We decreased pressure support from 5 to 0 cm H2O for 1 hr before extubation (stress test) while patients were on 5 cm H2O continuous positive airway pressure. Measurements and Main Results We measured respiratory frequency, tidal volume, ratio of respiratory frequency to tidal volume (f/Vt), airway occlusion pressure after onset of inspiration (P0.1), and gastric-arterial Pco2 (&Dgr;Pg-aco2) both on 5 cm H2O and 0 cm H2O pressure support. Then all patients were extubated. Failure of extubation was defined as reintubation within 24 hrs. Seventeen patients (25%) failed extubation. With pressure support of 5 cm H2O and continuous positive airway pressure of 5 cm H2O, most predictors were not different between patients who failed and patients who were successfully extubated. After the stress test, &Dgr;Pg-aco2 was 2 (−5; 15) mm Hg (median; quartiles) in successfully extubated patients vs. 28 (−9; 48) in failures (p = .0003), tidal volume was 473 (387; 558) vs. 400 (323; 435) mL (p = .02), and P0.1 was 2.8 (2; 4.1) vs. 4.1 (2.7; 5.3) mm Hg (p = .03), respectively. The stress test increased specificity of &Dgr;Pg-aco2 from 0.45 to 0.94 and positive predictive value from 0.85 to 0.97. The specificity and positive predictive values for f/Vt after the stress test were 0.23 and 0.78. Conclusions A simple stress test improves prediction of extubation outcome. &Dgr;Pg-aco2 has superior specificity and positive predictive value compared with other variables. The use of true clinical outcome (i.e., extubation) instead of the use of surrogate markers (e.g., tachypnea) distinguishes these results from previous studies.

External ventricular drains and mortality in patients with severe traumatic brain injury.

PURPOSE To determine our institutional adherence to the Brain Trauma Foundation guidelines with respect to intracranial pressure (ICP) monitoring, and examine the relationship between external ventricular drain (EVD) use and mortality. MATERIALS & METHODS Retrospective cohort study of 171 patients with severe traumatic brain injury (TBI). Propensity score adjusted logistic regression was used to model the association between EVD use and mortality. RESULTS EVDs were inserted in 98 of 171 patients. Of the 73 patients without an EVD, 63 (86%) would have qualified for ICP monitoring under the current guidelines. EVDs were in situ for a median of 8 days (SD 6). In adjusted analyses, EVD use was associated with hospital mortality (OR 2.8, 95% CI: 1.1 - 7.1, p = 0.04) and 28-day mortality (OR 2.1, 95% CI: 0.80 - 5.6, p = 0.13). We observed significant modification of the association between EVD and 28-day mortality by GCS within 12 hours (p-interaction = 0.04), indicating strong association only among those patients with GCS score of at least 6 (OR 5.0, 95% CI: 1.5 - 16.7, p < 0.01). CONCLUSIONS The association of EVD with 28-day mortality was only apparent among patients with GCS score of > or = 6. Further research is warranted to further refine which patients may benefit from ICP monitoring.

Volume expansion using pentastarch does not change gastric-arterial CO2 gradient or gastric intramucosal pH in patients who have sepsis syndrome.

Objective In hypovolemic patients with sepsis syndrome, to determine the effects of colloid volume infusion using 10% pentastarch on abnormal gastric tonometer measurements (gastric intramucosal CO2 tension, gastric intramucosal-arterial Pco2 gradient, and gastric intramucosal pH [pHi]) and on cardiac index, global oxygen delivery, and hemoglobin. Design Prospective prepost intervention study. Setting Tertiary care, university-affiliated 15-bed general systems intensive care unit. Patients Patients were studied who had sepsis syndrome, who had pulmonary arterial catheters in place, who were hypovolemic (pulmonary arterial occlusion pressure [PAOP] <15 mm Hg), and who had a gastric arterial Pco2 gradient >10 mm Hg. Interventions Baseline measurements of gastric intramucosal CO2 tension, gastric intramucosal-arterial Pco2 gradient, and pHi, as well as arterial lactate, pulmonary arterial occlusion, central venous and systemic arterial pressures, thermodilution cardiac output, and temperature. Boluses of 500 mL pentastarch were administered to a total of 1000 mL or until PAOP was >18 mm Hg. Measurements were repeated at 30 mins and 120 mins postinfusion of pentastarch. Main Results Volume infusion using pentastarch did not change gastric Pco2, gastric-arterial Pco2 gradient, or pHi. Volume expansion with pentastarch significantly increased cardiac index, global oxygen delivery, and PAOP. Administration of pentastarch decreased hemoglobin and arterial lactate at 30 mins but not at 120 mins. Conclusions Volume expansion using a colloidal solution of 10% pentastarch does not change abnormal intramucosal CO2 tension, gastric-arterial Pco2 gradient, or pHi in critically ill hypovolemic patients who have sepsis syndrome despite increasing cardiac index, oxygen delivery, and pulmonary artery occlusion pressure.