Best compliance during a decremental, but not incremental, positive end-expiratory pressure trial is related to open-lung positive end-expiratory pressure: a mathematical model of acute respiratory distress syndrome lungs.

A mathematical model of the acute respiratory distress syndrome (ARDS) lung, incorporating simulated gravitational superimposed pressure and alveolar opening and closing pressures, was used to study the mean tidal pressure-volume (PV) slope ("effective compliance") during incremental and decremental positive end-expiratory pressure (PEEP) trials with constant tidal volume (VT) "ventilation." During incremental PEEP, the PEEP giving maximum mean tidal PV slope did not coincide with "open lung PEEP" (minimum PEEP preventing end expiratory collapse of 97.5% of alveoli inflated at end-inspiration), and it varied greatly with varying VT and "lung mechanics." Incremental PEEP with a low VT tests recruitment by the peak pressure, not prevention of collapse by PEEP. During decremental PEEP with a low VT, maximum mean tidal PV slope occurred with PEEP 2-3.5 cm H2O below open-lung PEEP, unless closing pressure was high. High VT, high "specific compliance," and high opening pressures caused slightly greater underestimation of open-lung PEEP. Maximum mean tidal PV slope was always higher (e.g., 93.7 versus 16.69 ml/cm H2O), and the variation in PV slope with PEEP was greater, during decremental PEEP. The maximum PV slope during a decremental PEEP trial with a low VT may be a useful method to determine open-lung PEEP in ARDS, and should be studied clinically.

Extreme hypoventilation reduces ventilator-induced lung injury during ventilation with low positive end-expiratory pressure in saline-lavaged rabbits.

OBJECTIVE: To compare the degrees of ventilator-induced lung injury caused by two ventilation protocols. DESIGN: Randomized trial. SETTING: University animal laboratory. SUBJECTS: Sixteen New Zealand white rabbits. INTERVENTIONS: After five sequential saline lung lavages, eight pairs of anesthetized rabbits were allocated randomly to receive either of two ventilation protocols for 4 hrs during neuromuscular blockade. Both groups received 3 cm H2O of positive end-expiratory pressure and 100% oxygen. Control group animals received an estimated tidal volume of 12 mL/kg, an inspiratory time of 0.7 sec, and a ventilatory rate adjusted for a PaCO2 of 35 to 45 torr (4.7 to 6 kPa). Study group animals were ventilated through an intratracheal catheter, with inspiratory time of 1.5 secs, ventilatory rate of 20 breaths/min, and peak inspiratory pressure of 4 to 8 cm H2O, adjusted to maintain PaCO2 at 150 to 250 torr (20 to 33 kPa). MEASUREMENTS AND MAIN RESULTS: Arterial blood gases were measured every 30 mins. After 4 hrs, a final lung lavage was performed. Physiologic parameters, cell counts and protein concentration in the final lavage, and lung histology were compared between groups. The alveolar-arterial oxygen tension gradient was higher in the study group over the first 1.5 hrs, but the time profile showed significantly (p = .001) greater improvement in the study group. After 4 hrs, the mean alveolar-arterial oxygen tension gradient was lower in the study group (94 torr [12.5 kPa] vs. 201 torr [26.8 kPa]). The increase in neutrophil count from the initial to the final lung lavage was lower in the study group (0.27 x 10(7) cells/L vs. 2.01 x 10(7) cells/L, p = .037), as was the absolute value of the neutrophil count in the final lavage (1.33 x 10(7) cells/L vs. 3.02 x 10(7) cells/L, p = .04). The median hyaline membrane score was lower in the study group (0.5 vs. 3.0) but the difference was not statistically significant. CONCLUSION: These findings suggest that a very low tidal volume reduces ventilator-induced lung injury in saline-lavaged rabbits during ventilation at low lung volume.

The pressure-volume curve is greatly modified by recruitment. A mathematical model of ARDS lungs.

A mathematical model of the ARDS lung, with simulated gravitational superimposed pressure, evaluated the effect of varying alveolar threshold opening pressures (TOP), PEEP and peak inspiratory pressure (PIP) on the static pressure-volume (PV) curve. The lower inflection point (Pflex) was affected by SP and TOP, and did not accurately indicate PEEP required to prevent end-expiratory collapse. Reinflation of collapsed lung units (recruitment) continued on the linear portion of the PV curve, which had a slope at any volume greater than the total compliance of aerated alveoli. As recruitment diminished, the reduced PV slope could produce an upper Pflex at 20 to 30 cm H2O pressure. An upper Pflex caused by alveolar overdistension could be modified or eliminated by recruitment with high TOP. With constant PIP as PEEP increased, and TOP range of 5 to 60 cm H2O, PEEP to prevent end-expiratory collapse was indicated by minimum PV slope above 20 cm H2O, minimum hysteresis, and maximum volume at a pressure of 20 cm H2O. With constant inflation volume as PEEP increased, the effect on PV slope was unpredictable. Although increased PV slope indicated recruitment, maximum PV slope usually underestimated PEEP required to prevent end-expiratory collapse. Therefore, with this model the PV curve did not reliably predict optimal ventilator settings.

Pressure-limited ventilation with permissive hypercapnia and minimum PEEP in saline-lavaged rabbits allows progressive improvement in oxygenation, but does not avoid ventilator-induced lung injury.

OBJECTIVE: To determine whether pressure-limited intermittent mandatory ventilation with permissive hypercapnia and positive end-expiratory pressure (PEEP) titrated to arterial oxygen tension (PaO2) prevents or reduces acute lung injury, compared to conventional ventilation, in saline-lavaged rabbits. DESIGN: Prospective randomised trial. SETTING: University animal laboratory. SUBJECTS: 18 New Zealand White rabbits. INTERVENTIONS: Following five sequential saline lung lavages, anaesthetised rabbits were randomly allocated in pairs to receive either of two ventilation protocols using intermittent mandatory ventilation. The study group had peak inspiratory pressure limited to 15 cm H2O and arterial partial pressure of carbon dioxide (PaCO2) was allowed to rise. The control group received 12 ml/kg tidal volume with rate adjusted for normocarbia. PEEP and fractional inspired oxygen (FIO2) were adjusted to maintain, PaO2 between 8 and 13.3 kPa (60 and 100 mm Hg) using a predetermined protocol. At 10 h or following death, lung lavage was repeated and lung histology evaluated. MEASUREMENTS AND MAIN RESULTS: The mean increase in lavage cell counts and protein concentration and hyaline membrane scores were not significantly different between the groups. Oxygenation progressively improved more in the study group (p = 0.01 vs control for PaO2/FIO2 ratio and alveolar-arterial oxygen tension gradient (AaDO2)). PEEP was similar and the mean airway pressure higher in the control group, suggesting that this probably resulted from less ventilator-induced injury in the study group. Four deaths occurred in the control group (three due to pneumothorax and one to hypoxaemia) and none in the study group (p = 0.08). CONCLUSIONS: This ventilatory protocol may have failed to prevent lung overdistension or it may have provided insufficient PEEP to prevent injury in this model; PEEP greater than the lower inflection point of the pressure-volume curve has been shown to prevent injury almost entirely.

Permissive hypercapnia and gas exchange in lungs with high Qs/Qt: a mathematical model.

Low volume ventilation with permissive hypercapnia is becoming widely used in the treatment of acute respiratory distress syndrome. A mathematical model was developed to examine the effects of hypoventilation on pulmonary gas exchange in lungs with a range of shunt fractions. Hypoventilation did not worsen gas exchange, provided the inspired oxygen concentration was high enough to maintain PAO2 at an adequate level. In lungs with a high shunt fraction, some improvement in gas exchange may result, but these effects are small. A rightwards shift of the oxygen-haemoglobin dissociation curve induced by hypercapnia, is likely to be beneficial rather than detrimental in patients with acute respiratory distress syndrome. This analysis was limited to the direct effects of hypoventilation in lungs with constant shunt fractions, and did not encompass a number of possible secondary effects such as changes in cardiac output with PaCO2, changes in shunt fraction associated with a reduction in mean airway pressure and possible direct effects of hypercapnia on the pulmonary vasculature or airways.

Permissive hypercapnia in ARDS and its effect on tissue oxygenation.

Many experimental studies have shown that mechanical ventilation with high tidal volumes (Vt) or with a low end-expiratory volume allowing repeated end-expiratory collapse, can result in acute parenchymal lung injury and probably an inflammatory response. Low volume ventilation with permissive hypercapnia has been used in an attempt to avoid such injury in ARDS. Such management can affect oxygenation in many complex ways. The right-shift of the haemoglobin-oxygen dissociation curve during acute respiratory acidosis may increase venous oxygen tension (PvO2) which could allow increased O2 uptake in ischaemic tissues. Acidosis may reduce intrapulmonary shunt (Qs/Qt) by potentiating hypoxic pulmonary vasoconstriction, and there may also be direct and autonomically mediated effects of hypercapnia both on the lung vasculature and on the airways. Cardiac output usually increases as a consequence of hypercapnia and perhaps as a result of reduced intrathoracic pressure, further increasing PvO2 and CvO2, but the increase in cardiac output (CO) may tend to increase Qs/Qt as flow increases preferentially in unventilated lung. The reduction of mean airway pressure may directly increase Qs/Qt. Hypercapnia may affect the distribution of systemic blood flow both within organs and between organs. Limited clinical studies suggest that tissue oxygenation is usually unchanged or improved during permissive hypercapnia with increased CO, reduced arterio-venous O2 content difference and reduced blood lactate concentration. However, acute hypercapnia per se can reduce lactate production. Further studies are required of this complex issue.

Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercapnia: a prospective study.

OBJECTIVES: To evaluate the outcome in patients with severe adult respiratory distress syndrome (ARDS) managed with limitation of peak inspiratory pressure to 30 to 40 cm H2O, low tidal volumes (4 to 7 mL/kg), spontaneous breathing using synchronized intermittent mandatory ventilation from the start of ventilation, and permissive hypercapnia without the use of bicarbonate to buffer acidosis. Also, to compare hospital mortality rate with that predicted by the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system and the "ventilator score." SETTING: A ten-bed general intensive care unit in a university hospital. DESIGN: Prospective, descriptive study. PATIENTS: Fifty-three patients with severe ARDS having a lung injury score of > or = 2.5. INTERVENTIONS: Data recording. RESULTS: The hospital mortality rate was significantly lower than that predicted by the APACHE II scores (26.4% vs. 53.3%, p = .004), even after correcting the latter for the effect of hypercapnic acidosis (26.4% vs. 51.1%, p = .008). The mortality rate increased with increasing number of organ failures, but was only 43% in patients with > or = 4 organ failures, 20.5% with < or = 3 organ failures, and 6.6% with only respiratory failure. The mean maximum PaCO2 was 66.5 torr (range 38 to 158 torr [8.87 kPa, range 5.07 to 21.07]), and the mean arterial pH at the same time was 7.23 (range 6.79 to 7.45). There was no correlation between the maximum PaCO2 or the corresponding pH and the total respiratory rate at the same time. No pneumothoraces developed during mechanical ventilation. CONCLUSIONS: These results lend further support to the hypothesis that limitation of peak inspiratory pressure and reduction of regional lung overdistention by the use of low tidal volumes with permissive hypercapnia may reduce ventilator-induced lung injury and improve outcome in severe ARDS. This hypothesis is supported by a large body of experimental evidence, which also suggests that ventilator-induced lung injury may result in the release of inflammatory mediators, and thus may have the potential to augment the development of multiple organ dysfunction. However, the hypothesis requires testing in a randomized trial as acute hypercapnia could potentially have some adverse as well as beneficial effects.

What is the evidence for once-daily aminoglycoside therapy?

Aminoglycosides are important antibacterial agents for the treatment of serious infection. Evidence suggests that high peak plasma concentrations must be achieved early in the course of treatment if these agents are to be effective, but prolonged high concentrations may cause ototoxicity and nephrotoxicity. Peak plasma concentrations of 6 to 10 mg/L and trough concentrations of less than 2 mg/L for gentamicin and tobramycin have been traditional goals of therapy. Extensive recent evidence from in vitro, animal and human studies suggests that these target concentrations need revision. Aminoglycosides display concentration-dependent bacterial killing, have a long postantibiotic effect, and induce adaptive resistance in Gram-negative bacteria. All of these factors support the use of larger doses of aminoglycosides that are given less frequently than conventional therapy. Studies in vitro support this approach, showing greater activity when aminoglycosides are given less frequently. Animal studies comparing different dosage intervals have shown varying results, with only a slight bias favouring the longer dosage interval. However, the short elimination half-lives for the drugs in animals limit the applicability of these models to humans. Importantly, there is convincing evidence in animal studies that nephrotoxicity and ototoxicity are both reduced when the same total daily dose is administered in less frequent doses. There have been at least 29 clinical trials comparing once-daily administration of aminoglycosides with conventional administration 2 to 4 times daily. In general, efficacy has not been shown to be different between regimens, although one trial showed an advantage for once-daily administration compared with administration 3 times daily. A small number of trials have shown less nephrotoxicity and ototoxicity with once-daily administration, leading several authors to suggest that there is sufficient evidence to warrant a change to once-daily administration of aminoglycosides. However, once-daily administration has not been well studied in the paediatric population, or in patients with renal failure or endocarditis, and cannot be recommended in these patients as yet. The choice of a 24-hour dosage interval is somewhat arbitrary, and the optimal interval may not necessarily be 24 hours. No studies have included dosage adjustment based on pharmacokinetic modelling methods, and the effect of this on treatment outcome needs to be assessed. The best method of administering aminoglycosides once daily is yet to be determined.

Low volume ventilation with permissive hypercapnia in the Adult Respiratory Distress Syndrome.

Many animal studies have demonstrated that mechanical ventilation with high peak inspiratory pressures (PIP) can result in a form of acute lung injury closely resembling ARDS, ie characterised by hyaline membranes, granulocyte infiltration, increased pulmonary and systemic vascular permeability, and eventually proliferation of fibroblasts and type II pneumocytes. These studies have led to a concern that, in some patients, orthodox ventilatory management in severe ARDS may result in additional lung injury and, possibly, remote organ dysfunction. Mortality may be increased as a consequence. In an attempt to avoid such ventilator-induced lung injury in severe ARDS, several modifications of ventilatory management have been evaluated. We have previously reported the technique of low volume pressure limited ventilation with permissive hypercapnia, using tidal volumes of 5-7 ml/kg and allowing the PaCO 2 to rise substantially (maximum PaCO 2 17.2 kPa [129 mmHg]), mean maximum 8.3 kPa [62 mmHg]). In an uncontrolled study the mortality was significantly lower than that predicted by Apache II (16% vs 39.6%, p less than 0.01). Acute hypercapnia can cause many physiological disturbances but most of these appear to be due to the resulting intracellular acidosis and should not occur in hypercapnia of gradual onset, allowing the intracellular pH to be normalised. The time scales for compensation of intracellular and extracellular acidosis are markedly different. However, even severe acute hypercapnia appears to be remarkably well tolerated. Several clinical studies suggest that the avoidance of high PIP may reduce mortality in ARDS, but a randomised trial will be required to establish whether pressure limitation and permissive hypercapnia do improve outcome.

Serum aminoglycoside clearance is predicted as poorly by renal aminoglycoside clearance as by creatinine clearance in critically ill patients.

OBJECTIVE: To determine the relationships among serum aminoglycoside clearance, renal aminoglycoside clearance, measured creatinine clearance, and estimated creatinine clearance derived from a standard formula in critically ill patients. SETTING: A ten-bed general ICU in a university hospital. PATIENTS: Eighteen critically ill patients who were being treated with gentamicin or tobramycin for severe infections, and were hemodynamically stable. INTERVENTIONS: The various clearances were measured simultaneously after the administration of a dose of aminoglycoside by assaying serial blood samples for aminoglycoside and creatinine concentration, and by measuring the content of these substances in urine collected over the same time period. OUTCOME MEASURES: The slopes, intercepts and coefficients of determination (r2) of the various regressions were determined, along with the 95% confidence intervals for the prediction of serum aminoglycoside clearance from each other variable. RESULTS: Renal aminoglycoside clearance, creatinine clearance, and estimated creatinine clearance accounted for only 58%, 59%, and 62%, respectively, of the variance in serum aminoglycoside clearance. Only 64% of the variance in renal aminoglycoside clearance was explained by creatinine clearance. Substantial and variable nonrenal aminoglycoside clearance was evident. CONCLUSIONS: The 95% confidence intervals for the prediction of serum aminoglycoside clearance from each index of renal function indicated that none of these indices provided acceptable accuracy for the prediction of serum aminoglycoside clearance and dosage requirements in critically ill patients. Renal aminoglycoside clearance was not better than creatinine clearance in this respect, and thus no other index of renal function is likely to be more accurate. This finding implies that the only accurate method of determining the dose requirements to achieve target serum concentrations in such patients will be individualized pharmacokinetic dosing.

Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome.

Many animal studies have shown that high peak inspiratory pressures (PIP) during mechanical ventilation can induce acute lung injury with hyaline membranes. Since 1984 we have limited PIP in patients with ARDS by reducing tidal volume, allowing spontaneous breathing with SIMV and disregarding hypercapnia. Since 1987 50 patients with severe ARDS with a "lung injury score" greater than or equal to 2.5 and a mean PaO2/FiO2 ratio of 94 were managed in this manner. The mean maximum PaCO2 was 62 mmHg, the highest being 129 mmHg. The hospital mortality was significantly lower than that predicted by Apache II (16% vs. 39.6%, chi 2 = 11.64, p less than 0.001). Only one death was due to respiratory failure, caused by pneumocystis pneumonia. 10 patients had a "ventilator score" greater than 80, which has previously predicted 100% mortality from respiratory failure. Only 2 died, neither from respiratory failure. There was no significant difference in lung injury score, ventilator score, PaO2/FiO2 or maximum PaCO2 between survivors and non-survivors. We suggest that this ventilatory management may substantially reduce mortality in ARDS, particularly from respiratory failure.

Ventilatory management of ARDS: can it affect the outcome?

Animal studies have demonstrated that mechanical ventilation with high peak inspiratory pressure (PIP) results in acute lung injury characterised by hyaline membranes, granulocyte infiltration and increased pulmonary and systemic vascular permeability. This can result in progressive respiratory failure and death. In surfactant deficient lungs this occurs with tidal volumes (Vt) as low as 12 ml/kg, and PIP as low as 25 cm H2O, values which are frequently used clinically. The mechanisms resulting in this form of ventilator induced lung injury are not clear, but it appears to result from global or regional overdistension of the lung or terminal airways. It can be prevented or reduced in severity in some animal models by the use of PEEP. It is suggested that the use of high PIP in some patients may result in progressive deterioration of their ARDS, possibly contributing to mortality both from respiratory failure and other causes. It may be very important to limit PIP by reducing Vt even if this results in hypercapnia and a deterioration of oxygenation in the short term.

Assisted ventilation in severe childhood asthma.

Our experience of assisted ventilation in severe childhood asthma over a three year period is reviewed. One per cent of children with an acute attack of asthma required ventilatory support during this time. There were no deaths and no long term sequelae resulting from assisted ventilation. The number of children requiring this type of management however, provides further evidence to support the thesis that asthma is not only common but severe in New Zealand.

A retrospective survey of treatment and mortality in aspiration pneumonia.

A retrospective survey was conducted of all patients with severe aspiration pneumonitis requiring artificial ventilation in our Intensive Care Unit from 1982-1986 inclusive. Of 38 patients, 8 (21%) died. Five of these deaths were due to severe primary intracranial pathology, and occurred after complete or almost complete resolution of the pneumonitis. One death (2.5%) due to myocardial infarction was possibly related to aspiration, and 2 deaths (5%) were definitely related to aspiration. The 7.5% mortality related to aspiration is considerably lower than in previous clinical studies of severe aspiration pneumonia. There was only one death due to aspiration in patients under the age of 70. The mean arterial to alveolar oxygen tension ratio was 0.221, and the mean predicted mortality by apache II was 43%. Patients were managed with rapid intravascular volume restoration using crystalloid fluids, early ventilation, no steroids, and no immediate antibiotics. We conclude that with such management it is possible to achieve a low hospital mortality in severe aspiration pneumonia, particularly in young patients.

Extracorporeal CO2 Removal in severe adult respiratory distress syndrome.

Sixty-five per cent survival has been achieved in a group of patients with severe ARDS and a predicted mortality of 92%, by the use of Gattinoni's technique of extracorporeal CO2 removal. In patients and animals the technique has usually resulted in rapid improvement in the radiographic appearance and lung function. There are several possible mechanisms by which the technique may facilitate lung repair, including improvement of lung tissue oxygenation, the avoidance of high airway pressures and regional alkalosis in the lung, a reduction in oxygen toxicity, and the frequency observed reduction in pulmonary artery pressure. The apparent effectiveness of the technique and other associated evidence have implications which should lead us to reconsider some aspects of our conventional management of patients with severe ARDS.