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Physiologic integration, good timing, and short loop feedback.

As caregivers become aware of the time-weighted complexity of disease and treatment, the oft-quoted balance between medical art and science tips ever so slowly toward the latter. The first principle of healing is to avoid iatrogenesis. But what helps one patient may harm another--most treatments we apply present potential hazard. The response of our patients to the well intended interventions we apply depends on their stage of illness and adaptability, as well as on co-factors that determine therapeutic receptiveness and vulnerability. Our ability to assess the relative risk requires an understanding of physiology and disease evolution, as well as on sophisticated interpretation of key monitoring variables. Lacking one or more of these elements, the caregiver must proceed cautiously. Integration of multiple inputs, reasoned judgment as to what should be applied, adjusted, or withheld, and mid-course correction based on "short loop response feedback" are fundamental to effective ICU care. Simplified labels and toggle switch responses have their justified place in managing acute illness, but more often, securing a positive outcome calls for deeper understanding and involvement. An instructive example culled from my personal research interest and experience follows.

Ventilator Associated Lung Damage

The problem of avoiding ventilator-associated lung injury (VILI)--a very active field of investigation for two decades--illustrates the complexity of the problem, how sensitive it is to the severity and stage of underlying illness, and how naive we have been to assume that mastery of VILI avoidance can be achieved by adopting simple guidelines for setting PEEP and tidal volume. Our problem condition of acute lung injury/ARDS is not a single disease but an imprecisely identified process in continual evolution. Just as importantly, at any given time the response to our intervention depends not simply on the mechanical forces generated by a single tidal cycle, but also on the frequency with which they are applied and the metabolic and vascular environments in which they occur. Experimentally, temperature, PaCO2, minute ventilation and inspiratory flow magnitude and profile strongly influence VILI expression even as the same PEEP and tidal volume are applied. Perhaps the most potent of the VILI co-factors, however, are pulmonary vascular pressure and flows.

Mechanical forces that tear the delicate alveolar-capillary membrane can originate on either side of the boundary. Even though the great majority of investigative attention has been directed to airspace mechanics, the intra-luminal pressures applied to the airspace also impact the microvessels that surround it. Air and blood are separated by an incredibly thin barrier. Moreover, the behavior of alveolar and extra-alveolar vessels during lung expansion is fundamentally different. Even for the normal lung, inflation imposes competing vascular stresses on different classes of microvessels, and these stresses are amplified by the heterogeneity of acute lung injury.


Epithelial rupture causes the familiar forms of barotrauma that are evident radiographically; interstitial and alveolar hemorrhage caused by ventilation usually arises in the absence of radiographic barotrauma. Adverse ventilatory patterns applied to previously healthy lungs not only cause proteinaceous edema, but also neutrophil aggregation and hemorrhage, especially in the gravitationally dependent zones. The tendency for hemorrhage to occur preferentially in the most dependent regions of the lung during VILI may have several explanations. One compelling reason to expect microvascular disruption to occur there is that the mechanical stresses applied by the tidal inflation cycle are greatly amplified at the interface of opened and closed lung tissues. Another intriguing possibility to explain disproportionate vascular disruption in dependent lung regions is that dorsally situated tissues receive a majority of the lung's total blood flow and are subjected to greater hydrostatic pressures in the supine position. These higher intraluminal vascular pressures or flows might amplify tensile forces external to the microvessels or give rise to shearing stresses within the vascular endothelium that initiate inflammation-mediated tissue breakdown. There are hints in the early experimental literature addressing VILI that vascular pressure could play an important--if not pivotal role in VILI development or expression. Subsequent work has confirmed its centrality.

Vascular Contribution to VILI

Our own group has explored the vascular contribution to ventilator induced lung injury in a series of experiments using isolated ventilated and perfused (IVP) rodent lungs. I mention this because the IVP system offers numerous advantages for the investigation of the interactions between alveolar and vascular pressures that are uncontrollable or invisible at the bedside:

Taken together, our initial studies demonstrated that modifications of vascular pressure upstream from the alveolus could influence the severity of VILI inflicted by an unchanging adverse pattern of ventilation.

Having concluded from this early work that upstream microvascular pressure might be an important co-factor in the development of VILI, we next addressed the question of how the number of ventilatory cycles occurring over a timed interval influences the rate of edema formation or severity of histological alterations when maximum, minimum, and mean airway pressures are held identical.

We used our isolated, ventilated and perfused model in experiments testing the hypothesis that cumulative damage occurs as a function of the number of stress cycles as well as of stress magnitude. In other words, minute ventilation--not just tidal forces associated with tidal volume and PEEP-might be a controllable variable that influences VILI. Our experiments, as well as those of other labs, indicate that it is--in spades. While keeping the plateau, end-expiratory and inspiratory time fraction of all ventilation cycles constant, we varied the number of stress cycles to which these preparations were exposed over a given interval. Our main findings were that lungs ventilated at low frequencies and high peak pulmonary artery pressures formed less edema and displayed markedly less peri-vascular hemorrhage than did those ventilated at higher frequencies but identical peak pulmonary artery pressures Those data strongly indicated that not only are the characteristics of the tidal cycle and vascular pressures of fundamental importance to VILI, but also that minute ventilation, reflecting the number of stress cycles of a potentially damaging magnitude per unit time or their cumulative number, might be important, as well. It is important to emphasize that this implication applies only to tidal cycles driven by high inflation pressure and low PEEP. Knowing that the frequency of ventilation and vascular pressures are both important determinants of VILI expression, we reasoned that a Sung exposed to pulsatile vascular pressure but not ventilated might also experience significant injury, even without fluctuations of airway pressure. To summarize in a sentence--it did not. The interactions among airspace and vascular pressures are key. Without further exploration, one might have concluded that high vascular pressure was the essential VILI co-factor, but as later experiments indicate, it is the gradient of vascular pressure--a correlate of cardiac output and flow--that is most important.

Importance of VILI Co-Factors and Timing

What did we learn from all this lab research? Well, I think a lot. Because microvascular stresses appear to be a potent contributing variable in the development of the pulmonary edema and lung damage which may result from an injurious pattern of ventilation, raising pre-capillary microvascular pressure or reducing post capillary microvascular pressure are both undesirable when the lung is ventilated with high airway pressure. Under such conditions, raising ventilation frequency may also have a damaging cost. The implication is that reducing the subject's demands for blood flow and ventilation are lung protective approaches consistent with all of our data. Intriguingly, a recent clinical trial of muscle relaxants in the earliest stage of ARDS (very recently published in the New England Journal of Medicine) demonstrated mortality benefit from adopting that intervention. It is tempting for us to think that this otherwise astounding finding resulted from reductions of both minute ventilation and cardiac output in the phase of illness most vulnerable to VILI--but we don't know that. Later on, use of paralytics almost certainly flips to the dark side, as the vulnerability to VILI diminishes and muscular weakness is induced or amplified. As I see it, whether we consider employing dangerous drugs or potentially dangerous interventions such as mechanical ventilation, background predispositions and stage of illness matter greatly.

This lengthy example illustrates that collusion between vascular and airspace stresses might be needed to express VILI. Together, the lab and clinical data provide a rationale for aggressively reducing the ventilation and metabolic demands when we first confront patients in acute respiratory distress. Moreover, because interventions such as increasing PEEP, altering body position or extending inspiratory time may radically alter the microvascular environment, there is the prospect that benefit or unintended harm could arise from these maneuvers.

Wrapping It Up

In this final issue of FOCUS, I wish to transmit a message worthy of consideration as a "keeper". It is simply this: skillful management of the acutely ill is not implemented with diagnostic labels and therapeutic protocols alone, but with sound clinical judgment rooted in strong physiologic grounding and based on respect for disease complexity, awareness that acute diseases continue to evolve over time, and commitment to frequent mid-course corrections based on the patient's response to our best predictions of the moment. At least for now, medical practice must remain an empirical process.

Dr. Macini, Professor of Medicine at the Univ. of Minnesota, is a clinician-scientist whose investigative work has concentrated in the cardiopulmonary physiology and management of acute respiratory failure.

by John Marini MD
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Author:Marini, John
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Article Type:Report
Geographic Code:1USA
Date:Nov 1, 2010
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