Draft

200  Locke PGR Co2 Covid ARDS

200.1 Summary

  • How permissive, and for how long.
  • Case
  • PCO2?
  • Another Patient
  • What, if anything, should be done about this?
  • First Principles: What causes high CO2?
  • PaCO2 k VCO2 / VE (1-Vd/Vt)
  • Dead space in ARDS
  • Dead space in ARDS: Is COVID different?
  • Deadspace trajectory through ARDS

200.2 Slide outline

200.2.1 Slide 1

  • How permissive, and for how long.
  • Brian Locke MD
  • Fellow
  • C
  • 2 ### Slide 2
  • Case
  • 62 unvaccinated M was transferred from OSH after presenting with COVID-19 and DKA.
  • He was initially treated with meropenem->CTX, azithromycin, and vancomycin. For COVID-19, he received Remdesevir and Dexamethasone
  • 1 week into his hospitalization at the OSH, he was intubated and transferred to U of U
  • After transfer, he had the following sequence of chest imaging studies ### Slide 3
  • TODO: No text extracted from this slide. ### Slide 4
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  • PCO2? ### Slide 11
  • PCO2?
  • 2.2g CO2 1mol/44 g CO2 0.05 mol 50 mmol
  • 12 oz 355 mL
  • 50 mmol / 0.355 L 140 mmol/L
  • Cola Line ### Slide 12
  • TODO: No text extracted from this slide. ### Slide 13
  • Another Patient ### Slide 14
  • What, if anything, should be done about this?
  • Review of CO2 kinetics
  • Why does this happen? Dead space fraction in COVID-ARDS
  • Tolerating Hypercapnia: Pros and Cons
  • Review of control of ventilation related to hypercapnia and acidosis ### Slide 15
  • First Principles: What causes high CO2?
  • PaCO2 k VCO2 / VA
  • PaCO2 k VCO2 / VE (1-Vd/Vt)
  • If you hold VCO2 and Vd/Vt constant, you get the metabolic hyperbola (solid line) which relates PaCO2 to Ve ### Slide 16
  • PaCO2 k VCO2 / VE (1-Vd/Vt)
  • VCO2: doesn’t vary all that much in covid
  • VE: we are often (mostly) in control in this in the situation of COVID ARDS. In health, the body regulates this incredibly tightly.
  • More on this soon
  • Vd/Vt: is this uniquely bad in COVID-ARDS versus other ARDS?
  • Vd/Vt (PaCO2 - PECO2) / PaCO2 ### Slide 17
  • Dead space in ARDS
  • MIGET studies (10-15cc/kg days): Vd/Vt ~0.60 in severe ARDS
  • Estimate using PECO2 (~EtCO2) to PaCO2 ratio (requires blood gasses)
  • VD/VT (PaCO2-PECO2)/PaCO2
  • Ventilatory ratio (VR): [minute ventilation (ml/min) × PaCO2 (mm Hg)]/[predicted body weight × 100 (ml/min) × 37.5 (mm Hg)]
  • VCO2 estimated based on body size.
  • Index of impaired ventilatory efficiency that correlates with Vd/Vt ### Slide 18
  • What, if anything, should be done about this?
  • Review of CO2 kinetics
  • Why does this happen? Dead space fraction in COVID-ARDS
  • Tolerating Hypercapnia: Pros and Cons
  • Review of control of ventilation related to hypercapnia and acidosis ### Slide 19
  • Dead space in ARDS: Is COVID different?
  • Beloncle et al 2021: n112 COVID-19 ARDS matched to n198 non-COVID pulmonary ARDS
  • Matched on age, SAPS2 score, P:F, PEEP
  • Found Crs was no different. VR was lower in COVID-19 at day 1 compared to non-COVID, but increased to similar degree by day 7.
  • Luca Grieco et al 2021: n30 COVID-19 matched to n30 non-COVID ARDS
  • Matched on P:F, FiO2, PEEP, tidal volume
  • Ventilatory ratio (2.1 [1.7–2.3] vs. 1.6 [1.4–2.1], p 0.032) slightly higher in COVID-19 group
  • Conclusion: mixed but underwhelming differences
  • COVID-19 patients are often otherwise healthy, present with single organ failure
  • Non-COVID ARDS matched for the degree is likely to either die or be cured (antibiotics). Bias due to Survivorship and illness duration?
  • Possible COVID-ARDS evolves differently than other lung injury ### Slide 20
  • Deadspace trajectory through ARDS
  • https://twitter.com/danleisman/status/1468689855370702850?s11 ### Slide 21
  • Why is a normal PaCO2 33ish mmHg (SLC)?
  • Ventilation is metabolically expensive
  • work of breathing 2% of O2 at rest, but increases hugely with exercise or pathology
  • The same pH can be achieved at any PaCO2 by adjusting the bicarbonate: pH 6.1 + log [ HCO3 / (0.03 pCO2) ]
  • The existence of ‘compensation’ suggests pH is the defended variable
  • Why doesn’t the body operate with with a PaCO2 of 70? (and an HCO3 of 44 pH 7.42) This would be metabolically advantageous.
  • Especially in states where the work (power) of breathing is higher - such as lung disease
  • PaCO2 k VCO2 / VE (1-Vd/Vt)
  • VE (1-Vd/Vt) k VCO2 / PaCO2 ### Slide 22
  • Davenport Diagram: pH 6.1 + log [ HCO3 / (0.03 pCO2) ]
  • Hypoventilation
  • Renal Compensation
  • Why not live here? ### Slide 23
  • What actually happens in this process:
  • 3-5 days to reach steady state metabolic compensation in dogs; unknown time in humans
  • Acute: 0.1 mEq/L per 1 mmHg – modified some by pre-existing degree of HCO3. Not dependent on kidney
  • Chronic: 1960s – 0.35 to 0.4 mEq/L per 1mmHg Co2 increase; 0.48 - 0.51 mEq/L per 1mmHg more recently; depends on renal function.
  • Summarized in doi: 10.1053/ j.ajkd.2019.05.029 ### Slide 24
  • How much CO2 is ‘sequestered’? From https://doi.org/10.1152/jappl.2000.88.1.257 ### Slide 25
  • In a world without supplemental oxygen…
  • PAO2 (Patm – PH2O) FiO2 – (PaCO2 / RQ) + FiO2 PaCO2 (1-RQ)/RQ
  • (Patm – PH2O) FiO2 represents O2 arriving at the alveoli, which becomes saturated with H2O through the airways
  • PaCO2 / RQ represents the volume of O2 in the alveoli removed into the blood
  • FiO2 PaCO2 (1-RQ)/RQ represents the passive flow that must occur to maintain steady state when RQ / 1, because every O2 molecule leaving the alveoli is NOT replaced by 1 molecule of CO2.
  • Hypoventilation causes hypoxemia;
  • evolutionarily advantageous to have an oxygenation buffer?
  • severe hypercapnia is only possible with supplemental oxygen (Dalton’s Law) ### Slide 26
  • PAO2 (Patm – PH2O) FiO2 – (PaCO2 / RQ) + FiO2 PaCO2 (1-RQ)/RQ
  • Normal A-a gradient? 4 + (0.25 Age)
  • Critical PAO2 paO2 + (Normal A-a gradient) ### Slide 27
  • When we control the alveolar gasses…
  • At 100% FiO2, hypercapnia will almost never cause hypoxemia
  • PAO2 (Patm – PH2O) FiO2 – (PaCO2 / RQ) + FiO2 PaCO2 (1-RQ)/RQ
  • PaCO2 40: PAO2 (647 – 47) 1 – (40 / 0.8) + 1 40 (1-.8)/.8 556 mmHg
  • PaCO2 120: PAO2 (647 – 47) 1 – (120 / 0.8) + 1 120 (1-.8)/.8 534 mmHg
  • True effect might be different:
  • Moves O2-Dissociation curve to the right (could cause hypoxia)
  • Worsened V/Q matching (vasoconstriction in high VA zones) ### Slide 28
  • What, if anything, should be done about this?
  • Review of CO2 kinetics
  • Why does this happen? Dead space fraction in COVID-ARDS
  • Tolerating Hypercapnia: Pros and Cons
  • Review of control of ventilation related to hypercapnia and acidosis ### Slide 29
  • Argument for allowing hypercapnia
  • Could you ventilate at <6 cc/kg if you allow PaCO2 to increase?
  • k VCO2 / 40 mmHg vs k VCO2 /120 mmHg > 3x less VA; without the (probable) evolutionary reason we don’t do this (O2)
  • Direct Evidence: (Permissive Hypercapnia)
  • LTVV ARDS trials allow pH < 7.30 if RR 35+ or Pplat 25-30
  • What is attributable to the PHC, and what is the LTVV? Is PHC beneficial outside these indications? What about hypercapnia without acidosis? ### Slide 30
  • Is it the hypercapnia, or the severity of ARDS that leads to mortality?
  • Nin et al, 2017: 1998-2010, 1899 patients with ARDS
  • Maximum PaCO2 within 48h <30, 30-9, 40-9, 50-9, 60-9, 70+ mmHg
  • Multivariable Logistic regression: age, SAPS2, P/F, PEEP, RR, Acidosis, vent stg
  • Causal? Many other pertinent confounders (baseline CO2, lung disease, other management) ### Slide 31
  • Is it the hypercapnia, or the severity of ARDS that leads to mortality?
  • Muthu et al 2017: n415 with ARDS 2001-2016 at a single center
  • Multivariable logistic regression: APACHE2, pH, severity of ARDS
  • PaCO2 not independently associated with mortality (but pH is) ### Slide 32
  • TODO: No text extracted from this slide. ### Slide 33
  • CO2 ‘Narcosis’?
  • Less lipid soluble than N2;
  • CNS effects mediated by changes in intracellular pH and cerebral blood flow
  • Decreased LOC occurs when CO2 rises above 90-120 mmHg (Nunn’s and Lambs)
  • Likely contributes to encephalopathy in ICU patients
  • Adaptation almost certainly occurs
  • Healthy astronauts inhaling 8% CO2 (60 mmHg) experience > ### Slide 34
  • What, if anything, should be done about this?
  • Review of CO2 kinetics
  • Why does this happen? Dead space fraction in COVID-ARDS
  • Tolerating Hypercapnia: Pros and Cons
  • Review of control of ventilation related to hypercapnia and acidosis ### Slide 35
  • Sedation vacation:.
  • Will this patient feel more, less, or the same degree of dyspnea compared to a hypothetical patient with normal acid/base status? ### Slide 36
  • Ventilator Dyssynchrony
  • Anxiolysis, Analgesia, and ‘Respirolysis’ are only weakly related when assessed by P 0.1
  • https://journals.lww.com/ccmjournal/fulltext/2021/12000/managingpatientventilatordyssynchrony.18.aspx
  • https://journals.lww.com/ccmjournal/fulltext/2021/12000/discordancebetweenrespiratorydriveandsedation.9.aspx ### Slide 37
  • Haldane, Submarines, and Space Shuttles
  • What happens if you keep increasing FiCO2?
  • FiCO2 0 to 1.5%: VE increases, kidneys compensate, PaCO2 stable.
  • FICO2 1.5 to 3-6%: Partial renal compensation, VE increases to defend CO2
  • Bicarbonate excretion from kidneys 0, max renal effort (1963 - Operation Hideout).
  • FiCO2 3-6%+: somehow, the respiratory control system realizes it would be too costly to defend a given CO2 and PaCO2 levels are allowed to rise
  • This occurs before MVV
  • ’Comroe’s Law’ ### Slide 38
  • Drive to breath in 1 minute:
  • 4 sources:
  • Chemical drive – related to changes in arterial PO2 (NOT oxygen saturation), arterial and brain PCO2 and pH. Mediated by central and peripheral chemoreceptors.
  • Metabolic drive – related to metabolic rate and mediated by unknown mechanisms (e.g. how the Ve increases in CPET before blood gases change)
  • Wakefulness drive – disappears during sleep & anesthesia, a minor PaCO2 drop in presence of normoxia produces a central apnea
  • Voluntary / Supratentorial factors (anxiety hyperventilation, anticipation) ### Slide 39
  • Ventilatory Control
  • Central Chemoreceptors
  • Ventral surface of medulla
  • Responds to H+ in ECF of CNS – this equilibrates with CO2 in blood (no charge) more than pH in blood. CSF HCO3 lessens response. No O2 sensing. Slower response
  • Peripheral Chemoreceptors
  • Carotid and Aortic bodies.
  • Aortic body contributes to sympathetic and cardiovascular response
  • Respond (rapidly) to PaO2, PaCO2, and pH
  • Experiments injecting acids into CSF of animals leads to increase in VA
  • When PaCO2 and pH differ? (DKA) Mediated by metabolic drive to breath and peripheral chemoreceptor. ### Slide 40
  • Sensitivity of the controller system to CO2:
  • The PCO2/Ventilation Response ‘Curve’: straight/dashed line.
  • The amount that the respiratory system will respond to an increase in PaCO2
  • slope change in Ve / change in PaCO2
  • Steeper slope more sensitive, flatter less sensitive ### Slide 41
  • Might HCO3 buffering.. reduce dyspnea?
  • Brain curve (line): Ve that would occur if the respiratory system could do what the brain wants
  • Ventilation curve (line): Actual Ve
  • Dissociation of brain and ventilation curves -> dyspnea ### Slide 42
  • Returning to our patient:
  • Do you maximize VE within the parameters of ARMA to slowly correct? (RR 35, Plat 25-30)
  • Do you give acetazolamide?
  • Do you tolerate (or even encourage) hypercapnia to continue to minimize ventilator trauma and hope that eventually dead space improves? ### Slide 43
  • The lung: an ultra-kidney for volatile acids.
  • ‘CO2 Clearance’: Analagous to creatinine kinetics
  • Urine volume : VE (exhaled volume)
  • [Ucr] : FExhaled CO2
  • Serum creatinine : PaCO2
  • GFR : CO
  • Implication:
  • Further down on the ventilation axis, right on the PaCO2 axis, or R shifted the curve (increased VCO2 or Vd/Vt)
  • Larger the change in CO2 that will occur from a given change in Ve
  • Analogy: sCr of 6 is not much different than 5; PaCO2 70 not much different than 80
  • Yet, impacts of CO2 on hypoxemia, CNS, CV system, and drive to breathe may be linear. ### Slide 44
  • Does the PaCO2 ‘set-point’ change?
  • For example, in OHS:
  • Loop gain terminology primarily describes tendency toward stability of ventilation. ‘Gain’ of the feedback loop.
  • Controller gain: ventilatory response to PO2 and PCO2 )
  • Plant gain: changes in pulm capillary blood PO2 and PCO2 in response to changes in vent
  • Mixing gain: effective circulation time – time which cap blood changes are sensed by controller
  • Many changes are known to influence chemoreflex sensitivity
  • Ventillatory long-term facilitation is the process that should keep things on track
  • Ventilatory long-term facilitation is the term for adaptation to chronic stimulus (ie. sustained hypercapnia should increase loop gain to re-establish a baseline, and if this goes wrong you get a ‘wandering baseline’) ### Slide 45
  • Acetazolamide?
  • No effect in this RCT – OHS and COPD
  • https://pubmed.ncbi.nlm.nih.gov/28286047/ ### Slide 46
  • Post-script: meta-analysis
  • https://link.springer.com/article/10.1007/s00134-022-06640-1
  • Found conflicting results
  • Positive results from protective ventilation
  • Negative from effects on pulmonary vascular dysfxn ### Slide 47
  • https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-022-01006-8
  • COPD – ECCO2R
  • Faster normalization of blood gasses (CO2, pH) -> resolution of dyspnea. ### Slide 48
  • Editorial for https://link.springer.com/article/10.1007/s00134-022-06640-1
  • https://doi.org/10.1007/s00134-022-06696-z
  • They object to “induced” vs “permissive” hypercapnia done in the study

200.3 Learning objectives

  • How permissive, and for how long.
  • Case
  • PCO2?
  • Another Patient
  • What, if anything, should be done about this?

200.4 Bottom line / summary

  • How permissive, and for how long.
  • Case
  • PCO2?
  • Another Patient
  • What, if anything, should be done about this?

200.5 Approach

  1. TODO: Outline the initial assessment or decision point.
  2. TODO: Outline the next diagnostic or management step.
  3. TODO: Outline follow-up or escalation criteria.

200.6 Red flags / when to escalate

  • TODO: List red flags that require urgent escalation.

200.7 Common pitfalls

  • TODO: Capture common errors or missed steps.

200.8 References

TODO: Add landmark references or guideline citations.

200.9 Slides and assets

200.10 Source materials