Optimal respiratory rate to improve CO2 clearance during mechanical ventilation with restricted plateau pressure strategy

Dr.Vieillard-Baron and colleagues described that a increasing respiratory rate from 15 to 30 per minute with fixed plateau pressure (25cmH2O) during mechanical ventilation in patients with acute respiratory failure did not improve CO2 clearance, but produced dynamic hyperinflation, and impaired right ventricular ejection. And we doubt that whether there is a optimal respiratory rate with maximal CO2 clearance and find out how to calculate the optimal respiratory rate.

The end-inspiratory lung volume may be a fixed value in a patient with any given plateau pressure. If we always set plateau pressure as an endpoint of inspiration, we must decrease tidal volume to avoid high plateau pressure when respiratory rate increased and subsequently increased autoPEEP. Thus, tidal volume is not determined by inspiratory phase and is determined by the exhaled volume during expiratory phase.

In 1972, Bergman (2) studied the effect of increasing the mechanical-ventilator rate. Bergman stated, “For any patient, the minimum length of time needed for virtual completion of exhalation could be predicted from measurements of total respiratory compliance and resistance.”. He described it in the equation: V (t) = VO e^(–(1/RC)t), where V (t) is the volume of gas remaining in the thorax at any time in seconds (t) after exhalation, VO is the volume of gas in the thorax above resting expiratory level at the beginning of exhalation, and RC is the time constant for the respiratory system, which includes total resistance and compliance. Bergman showed that even in these normal lungs, gas trapping occurs at moderate increases in RR. To simplify the calculation, we define a variable j = e^(–(1/RC)) in any given patient and equation was transformed to V (t) = VO x j^t

With a given plateau pressure, there was constant V0. With a given patient, there was constant 1/RC and subsequently constant j. Thus, we could calculate the exhaled volume(tidal volume TV) in a given expiratory time(t) and V0.
TV = V0 - V(t) = V0(1- e^(–(1/RC)t)) or V0 (1-j^t)

However, there was no gas exchange in the total dead space(DV) and effective tidal volume(ETV) was calculated as
ETV= TV-DV = V0(1- e^(–(1/RC)t))-DV or V0 (1-j^t)-DV

Although, tidal volume was determined during expiratory phase, a respiratory cycle period(total time TT) includes inspiration time(Ti) and expiration time(t). TT=Ti + t
Thus respiratory rate(RR) = 60 / TT,
minute alveolar ventilation= RR x ETV = 60 x ETV / TT
Thus we must search for the maximal value of ETV/TT for maximal alveolar ventilation.

As illustrated in Fig-1, the slope from point A(-Ti,V0-DV) to any point over Bergman's equation was equal to ETV / TT, and the maximal slope was obtained by tangential line of expiratory curve through point A. When Ti and DV is fixed value, we could easily drawed the point A and obtained the optimal RR for maximal alveolar ventilation. From the data in the article by Dr.Vieillard-Baron and colleagues (1), we calculate optimal RR was approximately 22-23.

To increase respiratory rate from 15 to 30 with restriction of plateau pressure in there article, the total dead space was increased from 309 to 318mL (only 3% increase), tidal volume(TV) decreased from 596mL to 464mL, with expiratory time(t) decreased from 2.7sec to 1 sec and inspiratory time decreased from 1.3sec to 1 sec, inspiratory flow was from 458mL/sec to 464 mL/sec.
As previous described, TV = V0 (1-j^t), and we have 2 pair of (TV, t) data to substitute the equation, 596=V0 (1-j^2.7) AND 464=V0 (1-j).
We obtained V0=608mL and j=0.238, then the equation became TV = 608 x (1-0.238^t)

For nonsignificant change of total dead space and inspiratory flow, we assume the dead space(DV) as constant 310mL, and assumed inspiratory flow as constant 460mL/sec
Inspiratory time(Ti) = TV / inspiratory flow = 608 x (1-0.238^t)/460
TT= Ti + t = 608 x (1-0.238^t)/460 +t
ETV= V0 (1-j^t)-DV = 608 x (1-0.238^t) -310

Thus we could calculate RR and minute alveolar ventilation.
respiratory rate(RR) = 60 / TT = 60/(608 x (1-0.238^t)/460 +t)
minute alveolar ventilation(MV)= RR x ETV =60*(608*(1-0.238^t)-310)/(608*(1-0.238^t)/460+t)

With different expiratory time(t), we got different pairs of (RR, MV) and sketched figure 2. As illustrated in Figure 2, we found that maximal alveolar ventilation was 5114.2mL when expiratory time(t) was 1.479 sec, when TT was 2.64sec and RR was 22.7/min.
As in our mathematical model using data from article by Dr.Vieillard-Baron and colleagues (1), increase RR from 15 to 30, only increase alveolar ventilation from 4.3L/min to 4.5L/min, but increase RR from 15 to 22.7 may increase alveolar ventilation from 4.3 L/min to 5.1 L/min




REFERENCES
1.Vieillard-Baron A, Prin S, Augarde R, et al: Increasing respiratory rate to improve CO2 clearance during mechanical ventilation is not a panacea in acute respiratory failure. Crit Care Med 2002;30:1407–1412. PMID:12130953
2.Bergman NA: Intrapulmonary gas trapping during mechanical ventilation at rapid frequencies. Anesthesiology 1972;37:624–635. PMID:4652779

Role transition in ASCOT-BPLA trial

Atenolol decreased more than Amlodipine. Thiazide increased as Perindopril increased. The main opponent of perindopril in ASCOT seemed to be bendroflumethiazide.



ASCOT BPLA: Lancet 2005;366:895-906. PMID:16154016

Comparison between ASCOT-BPLA & ADVANCE

ASCOT BPLA
Duration 5.5years, 19257 people, 27% DM case
BP goal: non-DM 140/90, DM 130/80 =>average goal 137.3/77.3
Placebo BP start 163.9/94·5-> end 137.7/79.2 death 9%
Drug escalating, BP difference: 2.7/1.9mmHg
Hazard ratio: death (All 0.89 CV 0.76), Stroke 0.77
ADVANCE
Duration 4.3years, 11140 people, 100% DM case
BP goal: in discretion of physician (? 140/90)
Placebo BP start 145/81 -> end 140/73 death 8.5%
All medicated in active group, BP difference: 5.6/2.2mmHg
Hazard ratio: death (All 0.86, CV 0.82), Macro+micro 0.91

ASCOT BPLA: Lancet 2005; 366: 895–906. PMID:16154016
ADVANCE: Lancet. 2007 Sep 8;370(9590):829-40. PMID:17765963

Comment: ADVANCE lowered double SBP, but seems didn't have double benefit of ASCOT

Perindopril & Indapamide: Who played the key role in ADVANCE trial?

ADVANCE: Lancet. 2007 Sep 8;370(9590):829-40. PMID:17765963

ADVANCE trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. It showed significant outcome benefits including all-cause mortality, CV mortality, etc. To explain the source of outcome benefit in such a successful trial, we found that there was a large BP difference of 5.6/2.2mmHg between active and placebo groups.

In addition to BP lowering, it's reasonable to examine drug component difference between active and placebo groups retrospectively to explore the beyond BP effect, if there was any. We knew that the study drugs were perindopril and indapamide. And we would expect there was limited use of these drugs(ACEI&thiazide) in placebo group. When examining placebo group at end of follow-up, 55% of patients used perindopril when only 5% of patients used thiazides. As incomplete controlling of perindopril occured, outcome benefits of perindopril between groups may be halved. In contrast to perindopril, well-controlling of thiazide(indapamide) may reveal nearly full-strength outcome benefit, if there was any. It seems that indapamide played a greater role than perindopril in ADVANCE trial, whether positive or negative. And, we didn't know whether perindopril had a much more greater outcome benefits that even half of them overcame full-strength effects of indapamide.

Perindopril & Indapamide: Who played the key beneficial role in ADVANCE trial?
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