"Routine" Supportive Care in the ICU
Filtering Out the Bad News

Jesse Hall

Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois

	ARTICLE

TOP ARTICLE REFERENCES

Critical care medicine may be viewed as the application of monitoring modalities and minute-to-minute titrated therapy to stabilize patients with actual or threatened organ failures. As required and when appropriate, life support is instituted until underlying diseases are diagnosed or treated or recovery from trauma or surgical intervention occurs.

A large number of pharmacologic agents and technologies have become part of the armamentarium to achieve these goals muscle relaxants, anesthetic agents, hyperalimentation, mechanical ventilation, and dialysisto name but a few. In its infancy and rambunctious youth, critical care medicine borrowed such treatments broadly from other disciplines. Understandably, there was often a lack of complete evaluation of the new approach in the context of the intensive care unit (ICU). Over time, complications magnified by use of these treatments in the ICU were recognizedincluding protracted weakness after paralysis (1), delay in liberation from mechanical ventilation when continuous intravenous sedation was employed (2), and lung injury associated with ventilator support itself (3, 4). In the present more circumspect and mature phase of development of our field, we recognize that recovery from critical illness is something of a race between recovery from the precipitants of critical illness and accruing ICU complications. Thus, recognition of the complications of "routine" care and their pathophysiology is crucial to identify patients at risk and to minimize the incidence and effects of these complications.

In this issue of the Journal (pp. 514-520) there appears a study by Lehr and colleagues that is intriguing and provocative in this regard (5). These investigators documented the presence and studied the effect of particulate contaminants in intravenous antibiotic preparations. Using a light blockade particle counter technique as well as microscopy after filtration, they compared two generic preparations of cefotaxime sodium to a nongeneric product. They report a 30-fold increase of small particles (2 to 10 µm) and a 12- to 28-fold increase in large particles (25 to 100 µm) in the generic preparations as compared with the patented drug. These particulates were presumably organic and inorganic material contaminating the drug during manufacture or distribution.

The investigators then went on to study the effect of infusion of these particulates on the microcirculation in an animal model (5). The particulates recovered from each preparation were resuspended in saline and infused into hamsters. Functional capillary density was assessed in fine striated muscle using intravital fluorescence microscopy. In normal animals, no change in capillary density was observed after infusion of any of the preparations of resuspended particulate contaminants. If, however, the tissue bed was subjected to pressure-induced ischemia followed by reperfusion, subsequent injection of particulates recovered from the generic drug preparations caused a significant reduction in capillary density as compared with the nongeneric drug preparation or saline control. Histologic sections of the tissue in animals with capillary density loss revealed mechanical obstruction of the microcirculation by particulate material with an early inflammatory reaction.

What is the significance of these findings to the patient in the ICU? For those countries strictly adhering to Good Manufacturing Practice guidelines as required by federal regulations in the United States (6), these levels of contamination would not be encountered. In addition to a host of regulations controlling the specifics of drug manufacture, storage, distribution, and reconstitution at the clinical site, the standard use of 0.22-µm filters as required by these guidelines to achieve sterility eliminates essentially all particulates of the size described in this study. Thus, if this degree of contamination could lead to an adverse clinical effect, it would only be in health care environments lacking regulatory control or in instances of counterfeit drug use. The magnitude of unregulated or counterfeit drug use is, by its very nature, difficult to estimate.

In settings without adequate regulatory measures, it is conceivable that drug contaminants having even a mild adverse effect on microcirculatory function could be important, given the sheer volume of drug administration in the ICU. In one recent large multicenter study, the one-day point prevalence of infection in the ICU was 44.8%, almost half of which was acquired in the unit (7). Antibiotics are the most commonly prescribed drug class in the ICU (8), and increasing financial constraints make the use of generic products a widely employed cost containment strategy. Also, one must consider that particulate contamination may exist in other drug preparations, and intravenous infusion of drugs in general is likely greater in the ICU than in any other care setting.

What more can be said about the significance of this bench observation to patients? The muscle microcirculation of hamsters and humans is sufficiently similar in anatomy that one cannot reject these observations as a quirk of the species under consideration. Is ischemia-reperfusion in the animal a valid model of a patient in the ICU about to receive intravenous drug infusions? This question pertains to many bench investigations modeling critical illness and is best answered as "perhaps." Does the obstruction of the microcirculation in these animals constitute an injury that could result in a clinically adverse outcome in patients? This is difficult to determine, although the histologic evidence of an inflammatory response suggests this form of vaso-occlusion does trigger downstream events. Finally, is the quantity of particulates administered to these animalsthe amount recovered from filtration of a 1-g bottle of drugso excessive as to be irrelevant to conditions in the ICU? The authors make the point that our patients may indeed have a greater degree of baseline circulatory compromise related to trauma, sepsis, and their bedridden state, and that patients may receive drug infusions over a protracted period of time with large cumulative exposure to contaminants. In any event, the proper approach in assessing a potential insult to a biologic system experimentally is to exaggerate the effect at first pass and to establish the threshold for injury and its clinical relevance in subsequent work.

Thus, the work presented by Lehr and colleagues (5) raises many questions that could drive further study. I am reminded of one of the earliest studies (9) demonstrating microstructural injury of animal lungs subjected to brief periods of mechanical ventilation at high lung volume. At the time of publication, many wondered whether this curious observation had any relevance to the patients mechanically ventilated every day in the ICU. Before that connection was established, much further study at the bench was required (3), followed by careful clinical trials culminating in convincing evidence that avoidance of high tidal volume ventilation can improve outcome in patients with acute lung injury (4, 10). As the field moved from the early observation to bedside studies, more and more experts extolled the early study as insightful and important. It is difficult to pass judgment on the work of Lehr and colleagues (5) until we proceed along a similar path, and it is early yet to know how far we will travel. Alternatively, broad adoption of Good Manufacturing Practice guidelines could quickly and safely guarantee patient protection worldwide.

	References

TOP ARTICLE REFERENCES

1. Douglass JA, Tuxen DV, Horne M, Scheinkestel CD, Weinmann M, Czarny D, Bowes G. Myopathy in severe asthma. Am Rev Respir Dis 1992; 146: 517-520 [Medline].

2. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342: 1471-1477 [Abstract/Free Full Text].

3. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 1998; 157: 294-323 [Free Full Text].

4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342:1301-1308.

5. Lehr H-A, Brunner J, Rangoonwala R, Kirkpatrick CJ. Particulate matter contamination of intravenous antibiotics aggravates loss of functional capillary density in postischemic striated muscle. Am J Respir Crit Care Med 2002; 165: 514-520 [Abstract/Free Full Text].

6. 21 Code of Federal Regulations, Parts 210 and 211. http://www.fda.gov/cder/dmpq/cgmpregs.htm.

7. Vincent JL, Bihari DJ, Suter PM, Bruining HA, White J, Nicolas- Chanoin MH, Wolff M, Spencer RC, Hemmer M. The prevalence of nosocomial infection in intensive care units in Europe. Results of the European Prevalence of Infection in Intensive Care (EPIC) Study. JAMA 1995;274:639-644.

8. Gundlach CA, Faulkner TP, Souney PF. Drug usage patterns in the ICU: profile of a major metropolitan hospital and comparison with other ICUs. Hosp Formul 1991; 26: 132-136 [Medline].

9. Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures: protection by positive end expiratory pressure. Am Rev Respir Dis 1974; 110: 556-565 [Medline].

10. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, Kairalla RA, Deheinzelin D, Munoz C, Oliveira R, et al . Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 1998; 338: 347-354 [Abstract/Free Full Text].