In the Literature

The Hospitalist. 2007 February;2007(02):

February 1, 2007 | The Hospitalist

There was no difference in episodes of severe hypoglycemia in patients using inhaled insulin compared to those using subcutaneous insulin. A higher proportion of patients using inhaled insulin reported at least one episode of severe hypoglycemia compared to those using oral agents (risk ratio, 3.06 [CI 1.03 to 9.07]; 9.4% versus 3.5%, respectively).

With respect to pulmonary safety, all trials selected patients without histories of pulmonary problems and with at least six months of nonsmoking status. Pulmonary safety was assessed by self-reported symptoms and by pulmonary function tests. The most common pulmonary symptom associated with inhaled insulin was nonproductive cough. This symptom was reported more frequently compared to patients using subcutaneous insulin or oral agents (risk ratio, 3.52 [CI 2.23 to 5.56]; 16.9% versus 5.0%). Cough was noted early in the treatment course and diminished in frequency over time. Patients receiving inhaled insulin had a greater decrease in FEV1 (forced expiratory volume in the first second) from baseline than the comparator group (weighted mean difference, -0.031 L [CI-0.043 L to -0.020 L]). This decrease progressed slowly over the first six months but stabilized in studies of up to two years’ duration.

Only four trials reported data on overall patient satisfaction for inhaled insulin versus subcutaneous insulin. All trials reported a statistically significant increase in overall patient satisfaction with inhaled insulin over subcutaneous insulin. Patients randomly assigned to inhaled insulin were more likely to continue taking inhaled insulin than to switch back to subcutaneous insulin.

Conclusions

This meta-analysis showed that inhaled insulin is comparable to subcutaneous insulin in lowering hemoglobin A1C levels in patients with type 1 or type 2 diabetes. The proportion of patients reaching a target hemoglobin A1C of less than 7% was much lower in the studies in this meta-analysis as compared to levels in trials of intensive subcutaneous insulin therapy.

It’s more difficult to compare inhaled insulin with oral hypoglycemic agents because most studies involving oral agents used fixed dosing with different types of oral agents. There was a three-fold risk of severe hypoglycemia in patients using inhaled insulin compared to those using oral hypoglycemic agents. This is probably due to overall improved glycemic control in the inhaled insulin group. Cough was more common in the inhaled insulin groups, and there were small decreases in FEV1, but these did not progress over two years. The potential for pulmonary toxicity with long-term administration has not been evaluated and deserves further study.

Classic Literature

A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care

Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-417.

Background

There are important risks and benefits of red cell transfusion in critically ill patients. One concern is that anemia may not be tolerated well in this group. Because red cell transfusions are used to augment the delivery of oxygen to avoid the harmful effects of oxygen debt, transfusing patients to keep their hemoglobin levels higher than 10.0 g per deciliter has become a routine practice. There is concern, however, that critically ill patients may be at increased risk of immunosuppressive and microcirculatory complications of red cell transfusions. Also, concern about the safety and supply of red cell transfusions has encouraged a more conservative approach to transfusion strategies.

The authors of this study conducted a randomized, controlled, clinical trial involving critically ill patients with euvolemia to determine whether a restrictive transfusion strategy that maintains hemoglobin concentrations between 7.0 and 9.0 g per deciliter was equivalent to a liberal strategy of maintaining hemoglobin concentrations between 10.0 and 12.0 g per deciliter.

Methods

Enrolled patients were admitted to 25 different intensive care units in Canada between 1994 and 1997. Included patients were expected to have an intensive care unit stay longer than 24 hours and a hemoglobin concentration of 9.0 g per deciliter or less within 72 hours after admission and were considered euvolemic after initial treatment by physicians. Critically ill patients with euvolemia were randomized to either the restrictive or the liberal strategy. Patients were given one unit at a time, and the hemoglobin concentration was measured after each unit transfused. Transfusion was stopped when the patient’s hemoglobin concentration was in the target range. The primary outcome was death from all causes within 30 days of randomization.

Results

A total of 838 patients were enrolled in the study; 418 in the restrictive group and 420 in the liberal group. The average daily hemoglobin concentrations were 8.5 g per deciliter in the restrictive group and 10.7 g per deciliter in the liberal group (P<0.01). An average of 2.6 red cell units per patient was transfused in the restrictive group, as compared to an average of 5.6 red cell units in the liberal group (P<0.01). Thirty-three percent of patients in the restrictive group did not receive any transfusion; every patient in the liberal group received at least one red cell unit.

The rate of death from all causes in the 30 days after admission was 18.7% in the restrictive group and 23.3% in the liberal group (-0.84% to 10.2%, P=0.11). The inpatient mortality rates were lower in the restrictive group (22.2% versus 28.1%, P=0.05). More patients in the liberal group had some type of cardiac complication (21.0% versus 13.2% respectively, P<0.01). Subgroup analyses demonstrated that patients with lower APACHE II scores (20 or less) and patients younger than 55 had improved survival in the restrictive strategy group. There were no significant differences in 30-day mortality between treatment groups in the subgroup of patients with a primary or secondary diagnosis of cardiac disease (20.5% in the restrictive group and 22.9% in the liberal group, P=0.69).

Conclusions

The findings in this study indicate that the use of a restrictive red cell transfusion strategy to hemoglobin levels as low as 7.0 g per deciliter, combined with the maintenance of hemoglobin concentrations between 7.0 and 9.0 g per deciliter, was at least as effective as a more liberal strategy in critically ill patients with euvolemia. All-cause 30-day mortality was no different between the groups but favored the restrictive strategy. The rates of inpatient deaths were lower in the restrictive group. There were more cardiac complications in the liberal group. An important subgroup of patients, those with a history of cardiac disease, had no differences in mortality. The use of this strategy decreased the average number of red cell transfusions by 54%. TH