LITERATURE MONITOR FOR CRITICAL CARE

TWO DRUGS SHOW NO BENEFIT FOR ARDS OR SPESIS

Yet another two agents have failed to lower mortality in patients with acute respiratory distress syndrome (ARDS) or sepsis. Ketoconazole showed no benefit in the early treatment of acute lung injury or ARDS, and the platelet-activating factor receptor antagonist BB-882 did not improve outcome in patients with sepsis.

In the ketoconazole study, 234 patients with early acute lung injury or ARDS were randomized to 400 mg/d ketoconazole or placebo for up to 21 days. The patients were followed for 28 days.

While ketoconazole was found to be safe and bioavailable, it did not improve survival rates, the number of ventilator-free days, the number of organ failure-free days, or any measure of lung function. These findings conflict with those from three smaller clinical studies.

In the BB-882 trial, 152 patients with sepsis and a mean APACHE II score of 15 to 35 in the 24 hours before study entry were randomized to BB-882 or placebo. A 4-mg loading dose of BB-882 was given on the first day, followed by an intravenous infusion of 96 mg/24 hours for up to 120 hours.

The drug showed no advantage over placebo in terms of survival after 28 days, hemodynamic status, respiratory function, or organ failure scores. The findings confirm the results of other clinical studies using platelet-activating factor receptor antagonists.

Ketoconazole for early treatment of acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. The ARDS Network. JAMA. 2000;283: 1995-2002.
Vincent JL, Spapen H, Bakker J, et al. Phase II multicenter clinical study of the platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis. Crit Care Med. 2000;28:638-642.

ß-AGONISTS AND MYOCARDIAL INFARCTION

Physicians may want to use caution when prescribing inhaled ß-agonists to patients with cardiovascular disease. A new study has shown that in such patients, these agents increase the risk of myocardial infarction.

Au et al studied the medical records of 1,444 patients who had suffered a myocardial infarction and 4,094 randomly selected controls who were enrolled in the same health maintenance organization as the patients. The patients and controls were matched for age, sex, hypertension status, and index date. A computerized pharmacy database was used to determine how many subjects had filled prescriptions for an inhaled ß-agonist.

Subjects who did so in the three-month period before the index date had a 67% higher risk of myocardial infarction than did those who had not filled a prescription. However, further investigation showed that this increased risk was found only in subjects who had a history of cardiovascular disease.

Among patients with a history of cardiovascular disease, the adjusted odds ratio for myocardial infarction was 3.22 for those who had filled a prescription for an inhaled ß-agonist within three months of the index date (the comparison was made with those who had not filled a prescription in the past three months). The risk was even higher among first-time users of ß-agonists with a history of cardiovascular disease (see Figure 1). The risk did not increase further with greater number of prescriptions filled.

Au DH, Lemaitre RN, Curtis JR, et al. The risk of myocardial infarction associated with inhaled ß-adrenoceptor agonists. Am J Respir Crit Care Med. 2000; 161:827-830.

MECHANICAL VENTILATION AROUND THE GLOBE

The primary indications for mechanical ventilation are uniform across the globe. However, the modes of mechanical ventilation and the methods of weaning vary considerably from country to country.

These variations were uncovered by Esteban et al in a prospective study of ventilator use in intensive care units in North America, South America, Spain, and Portugal. The investigators collected data on patient demographics, ventilator indications, ventilator data, and physician preference on ventilator mode and weaning methods.

Indications for the initiation of mechanical ventilation varied little at the different sites and included respiratory failure (66% of patients), coma (15%), acute exacerbation of chronic obstructive pulmonary disease (13%), and neuromuscular disorders (5%). Ventilator settings were also similar; tidal volumes ranged from 7 to 10 mL/kg and positive end-expiratory pressure was usually kept at 5 cm H2O.

However, physicians in the United States and Canada were less likely than their colleagues in most of the other countries surveyed to use assist/control ventilation and somewhat more likely to use the combination of synchronized intermittent mechanical ventilation and pressure support. Esteban et al also found that many of the newer modes of ventilation, such as synchronized intermittent mandatory ventilation as a stand-alone mode, noninvasive ventilation, and permissive hypercapnia, were used infrequently in most countries.

About one third of the patients were undergoing an attempt at weaning at the time of the study or had undergone such an attempt within the preceding 24 hours. The weaning method varied from country to country; for example, pressure support was used in 45% of weaning attempts in the US and Canada but in only 23% of those in Spain. Intermittent trials of spontaneous breathing were attempted in almost 40% of patients in Spain and Portugal but in only 6% of North American patients.

"The results suggest that findings from research on mechanical ventilation and weaning are incorporated into clinical practice at a very slow pace," according to Esteban et al.

Esteban A, Anzueto A, Alia I, et al. How is mechanical ventilation employed in the intensive care unit? An international utilization review. Am J Respir Crit Care Med. 2000;161:1450-1458.

A FASTER TEST FOR DIAGNOSING NOSOCOMIAL PNEUMONIA

Counting the percentage of infected cells in a bronchoalveolar lavage specimen is the only test whose predictive value is sufficiently high to guide the initial antibiotic choice in patients with suspected nosocomial pneumonia, a recent prospective study suggests.

Veber et al examined the predictive value of three types of bronchoscopy specimen analysis to determine which was most helpful in guiding antibiotic selection before qualitative culture results were available:

• Direct examination of bronchial aspirate.
• Direct examination of plugged telescopic catheter specimens.
• Direct examination and estimation of infected cell counts from bronchoalveolar lavage specimens. (In this technique, a specific percentage of cells--at least 3%--had to contain intracellular bacteria.)

The study subjects included 64 patients with suspected nosocomial pneumonia who were hospitalized for more than 48 hours. A diagnosis of nosocomial pneumonia was established in 46 patients through a review of all clinical, radiologic, laboratory, and microbiologic data collected one month after the bronchoscopy.

The sensitivity and specificity of the three sampling techniques are shown in Table 1. Direct examination of bronchoalveolar lavage specimens using a 3% cutoff for infected cells had a significantly higher positive predictive value than the other two procedures.

Subgroup analysis of patients from whom all three specimen types were collected during the same bronchoscopy procedure showed that combining direct examination of a plugged telescopic catheter specimen with an infected cell count from a bronchoalveolar lavage specimen improved sensitivity to 83%.

Veber B, Souweine B, Gachot B, et al. Comparison of direct examination of three types of bronchoscopy specimens used to diagnose nosocomial pneumonia. Crit Care Med. 2000;28:962-968.

VASOPRESSORS DO NOT BENEFIT PATIENTS WITH MULTIPLE ORGAN FAILURE

While norepinephrine and other potent vasopressors may be of use in the treatment of severe hypotension in some patients with circulatory shock, these agents appear to offer no benefit to patients who already have multiple organ dysfunction, according to new findings.

Abid et al retrospectively studied the medical records of 100 consecutive patients who were treated with norepinephrine for severe hypotension. All of the patients showed evidence of circulatory shock and altered hypoperfusion refractory to fluid administration and dopamine treatment.

Both the time before starting norepinephrine treatment after admission to the intensive care unit (ICU) and the degree of organ dysfunction affected outcome. In fact, all 30 patients with the following characteristics died: initiation of norepinephrine treatment more than one day after ICU admission and a total sequential organ failure assessment score of more than 12. In the rest of the group, mortality rates ranged from 55% to 71%.

"Our findings do not suggest that norepinephrine treatment is of no use in the ICU, but that it may be ineffective in certain patients with [multiple organ failure]," Abid et al concluded.

Abid O, Akça S, Haji-Michael P, Vincent JL. Strong vasopressor support may be futile in the intensive care unit patient with multiple organ failure. Crit Care Med. 2000;28:947-949.

PERC TRACH IS SAFE FOR OBESE PATIENTS

Percutaneous dilatational tracheostomy is a safe and effective alternative to surgical tracheostomy in obese patients with persistent respiratory failure.

These findings are based on a case review of 13 consecutive obese patients (age 18 years and older) who required tracheostomy for persistent respiratory failure requiring continued mechanical ventilation. All of the patients consented to bedside percutaneous dilatational tracheostomy.

The procedure was successfully performed in all patients. The only complications were paratracheal placement of the tracheostomy tube in one patient and a cuff leak in one patient on day 2 following the procedure.

Obese patients with large and thick necks are usually referred for surgical tracheostomy because they are considered poor candidates for percutaneous dilatational tracheostomy. However, these findings suggest that the latter procedure, when performed by experienced physicians, may be associated with a high success rate, a low complication rate, and a cost reduction in the treatment of obese patients.

Mansharamani NG, Koziel H, Garland R, et al. Safety of bedside percutaneous dilatational tracheostomy in obese patients in the ICU. Chest. 2000;117:1426-1429.

IMMUNE-ENHANCING DIET BENEFITS PATIENTS WITH SEPSIS

An immune-enhancing enteral diet significantly reduced the mortality and infection rate among patients with sepsis, according to findings from a recent prospective trial. These reductions were greater among patients with APACHE II scores of 10 to 15 than among those with higher scores.

Galbán et al randomized 176 patients with sepsis and APACHE II scores of 10 or more to an enteral formula enriched with arginine, messenger RNA, and omega-3 fatty acids from fish oil, or to standard enteral nutrition (control). In both formulas, 22% of calories were from protein. The diets were started within 36 hours of the diagnosis of sepsis and had to reach the caloric target by day 4. The two patient groups were similar in terms of age, height, ideal weight, gender, and APACHE II score at intensive care unit (ICU) admission.

The mortality rate was found to be significantly lower in the treatment group than in the control group (19% vs 32%). This beneficial effect of the immunonutrition diet was even stronger in patients with lower APACHE II scores at the time of ICU admission. In fact, among the patients with APACHE II score of 10 to 15, only 4% of patients in the treatment group died, versus 28% of control patients.

Significantly fewer of the patients in the treatment group than in the control group experienced bacteremia (8% vs 22%). While the two groups had a similar number of nosocomial infections, a significantly greater proportion of patients in the control group acquired more than one nosocomial infection.

"The study represents the first time that immunonutrition has been convincingly shown to reduce mortality rate," noted Adrian Barbul, MD, in an accompanying editorial. The benefits found in this study "may remove one objection to the use of immunonutrition, namely, a cost that is eight to ten times higher than that of standard formulations," he added.

Galbán C, Montejo JC, Mesejo A, et al. An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients. Crit Care Med. 2000;28:643-648.
Barbul A. Immunonutrition comes of age. Crit Care Med. 2000;28:884-885.

ANTIBIOTIC CHOICE FOR COPD EXACERBATION

Antibiotic choice does not affect treatment outcome in patients with chronic obstructive pulmonary disease (COPD), according to data from a retrospective analysis. Instead, treatment failure was associated with the severity of the underlying disease and the frequency and severity of symptoms.

Dewan et al reviewed medical charts from 107 outpatients who were treated with antibiotics for an acute exacerbation of COPD. The patients were followed for 24 months from the time of the exacerbation. Treatment failure was defined as the presence of persistent respiratory symptoms that required an antibiotic change within four weeks. About three fourths of all exacerbations were treated with first-line antibiotics.

Treatment failure occurred in 12.1% of first exacerbations and 14.7% of all exacerbations. The following factors were independently associated with treatment failure: a forced expiratory volume in one second below 35%, history of pneumonia, history of sinusitis, use of maintenance corticosteroids, use of home oxygen, and a high frequency of exacerbation. The latter two factors were the strongest predictors of treatment failure.

"Surprisingly, age, the presence of comorbidity, and the choice of an antibiotic did not affect the treatment outcome," Dewan et al noted. However, they could not rule out the possibility that newer antibiotics may improve outcome, as these agents were used in only a small percentage (22%) of the patients in this study.

Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation of COPD: factors associated with poor treatment outcome. Chest. 2000;117:662-671.

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