Mervyn Singer Bloomsbury Institute of Intensive Care Medicine,

Mervyn SingerBloomsbury Institute of Intensive Care Medicine,University College London, UK

Monitoring the adequacy of organ perfusion & function in shock

Monitoring the adequacy of organ perfusion & function in shock

Declarations of potential conflicts ..Declarations of potential conflicts ..

(Deltex)(Edwards)Oxford Optronix - free probes

ShockShock

Delivery to, or utilisation of, oxygen that is inadequate to meet the cells’ metabolic needs

Shock - a physiological definitionShock - a physiological definition

o hypoxic hypoxia (low PO2)

o circulatory hypoxia (low CO)

o anaemic hypoxia (low Hb)

o cytotoxic dysoxia (mitochondrial

dysfunction) VO2VO2

DO2DO2O2O2

‘Perfusion’ vs ‘Adequacy of perfusion’‘Perfusion’ vs ‘Adequacy of perfusion’

Perfusion = oxygen delivery • flow (macro- & microcirculation)• Hb• SO2 (local PO2)

Adequacy of perfusion =perfusion enough to supply tissues

adequately

Perfusion/Adequacy of perfusionPerfusion/Adequacy of perfusion

o biochemicalo lactateo base deficit

o vascular and tissue respiratory gaseso CO2 - tissue tensiono O2 - venous, tissue, microvascular - tissue tension, saturation, VO2

o microcirculationo mitochondrial redox status

LactateLactate

o [lactate] predictive of poor outcome in …sepsis, trauma, haemorrhageo very non-specific marker of tissue hypoxia o more due to metabolic effects of epinephrine …than reduced tissue perfusion o related to ∆ muscle Na+/K+-ATPase activity …driven by epinephrine-stim’d aerobic glycolysiso high [lactate] & [epinephrine] can persist for …weeks in burn-injured patients

HyperlactataemiaHyperlactataemia

o .. blocked by ouabain or ß-blockero iatrogenic causes

o lactate-buffered haemofiltrationo epinephrineo drugs e.g. NRTIs

o non-shock causeso severe liver dysfunctiono ∆ muscle protein degradation

Arterial base deficitArterial base deficit

= amount of base (mmol) required to titrate 1 litre of whole blood to a normal pH, assuming normal physiological values of PaO2, PaCO2 and temperature.

Arterial base deficitArterial base deficit

o ∆ H+ ion production in shock related to … ..∆ hydrolysis of ATPo arterial base deficit predictive of poor outcome … in sepsis, trauma, haemorrhageo many non-hypoxic causes of metabolic acidosis

o renal dysfunctiono liver dysfunction o drug toxicity (e.g. cocaine)o bicarbonate loss (e.g. diarrhoea) o hyperchloraemia …

n.b. starting value of base excess may ‘camouflage’

SUMMARY: base deficit/lactateSUMMARY: base deficit/lactate

o good early prognosticators in shock states

o good early guide to therapeutic response

o good sensitivity

o poor specificity to shock & assessment of

perfusion - many confounders (patient/iatrogenic)

Tissue PCO2Tissue PCO2

o gut tonometry

o sublingual capnometry

H+

local metabolic acidosis(acid buffered by tissue HCO3

-)

HCO3-

pCO2

local respiratory acidosis (stagnant flow)pCO2

Tissue PCO2 - traditional viewTissue PCO2 - traditional view

Gutierrez G. Blood flow, not hypoxia, determines intramucosal PCO2. Crit Care 2005; 9:149-50

pHi = 6.1 + log HCO3-

(0.03 x PCO2)

Henderson-Hasselbalch equationHenderson-Hasselbalch equation

Tissue pCO2 Tissue-arterial pCO2 gapTissue-end-tidal pCO2 gap

Gastric pHi - prognosticatorGastric pHi - prognosticator

Low pHi related to poor outcome• Doglio (CCM ‘91)• Maynard (JAMA ‘93)• Mythen (ICM ‘94)

Low pHi related to inability to wean• Mohsenifar (Ann Intern Med ‘93)

Gastric pHi-guided therapy??Gastric pHi-guided therapy??

pHi-guided Rx improved outcome in ICU

subset• Gutierrez (Lancet ‘92)

… or doesn’t• Gomersall (Crit Care Med 2000)

SUMMARY: tissue PCO2SUMMARY: tissue PCO2

o methodological/practical issues to be resolvedo marker of poor regional perfusiono relevance to other regional circulations??o reasonable prognostic tool (as good/better than lactate/base deficit)o ability to direct therapy & improve outcome???o much hype in the 1990s .. why so quiet now??

OxygenOxygen

o mixed/central venous O2 saturation

o tissue oxygen tension & saturation

o oxygen consumption

Mixed/central venous O2 saturationMixed/central venous O2 saturation

o marker of global supply/demand balanceo falls in low output states e.g. heart failureo prognosticator of outcome, failure to wean…o elevated in resuscitated sepsis

o microvascular shunting??o decreased cellular utilisation??

o mixed venous vs central venous differenceso one landmark ScvO2-targetted study

(Rivers)

SUMMARY: mixed/central SvO2SUMMARY: mixed/central SvO2

o PA catheter use decline .. ∆ reliance on ScvO2

o Rivers’ study needs repeating - recently fundedo Useful in global low output stateso Limited in established sepsis (other than identification of low values)

Tissue O2 tensionTissue O2 tension

o marker of local supply/demand balanceo measurable with various technologies

o optode, Clark electrode, NIRS, EPR oximetry ..

o falls in low output states e.g. heart failureo elevated in resuscitated sepsiso studied separately in multiple tissue beds

o gut mucosa, skeletal muscle, bladder, brain, kidney (animal)o brain, skeletal muscle, conjuctiva, subcutaneously (man)

Boekstegers et al, Shock 1994;1:246-53

Muscle tissue pO2 in septic patientsMuscle tissue pO2 in septic patients

controlcontrol

cardiogenic shockcardiogenic shock

limited infectionlimited infection

sepsissepsis

00 2020 4040 6060

Tissue pO2 (mmHg)Tissue pO2 (mmHg)

Rosser et al. J Appl Physiol 1995; 79: 1878Singer et al. Intensive Care Med 1996; 22: 324Stidwill et al. Intensive Care Med 1998; 24: 1209

Rosser et al. J Appl Physiol 1995; 79: 1878Singer et al. Intensive Care Med 1996; 22: 324Stidwill et al. Intensive Care Med 1998; 24: 1209

HaemorrhageHaemorrhage

ResuscitationResuscitation HypoxaemiaHypoxaemia21% O221% O2

15% O215% O2 10% O210% O2

6% O26% O2

Bladder tissue pO2 falls in other shock statesBladder tissue pO2 falls in other shock states

00

44

88

1212

1616

00 11 22 33time (h)time (h)

Bladder epithelial PO2 (kPa)Bladder epithelial PO2 (kPa)

Endotoxin

Control

o no organ-organ comparisons publishedo influence of inspired oxygen in shock states?o impact of volume of tissue being sampled

o probe size/surface area

o multi-array electrodes…

Tissue O2 tensionTissue O2 tension

Acute response in tissue PO2 to bolus of LPS (10 mg/kg)Acute response in tissue PO2 to bolus of LPS (10 mg/kg)

20

30

40

50

60

70

80

20

30

40

50

60

70

80

0

10

20

30

40

0 1 2 30

10

20

30

40

0 1 2 3

Time post-LPS (h)Time post-LPS (h)

Muscle Bladder

KidneyLiver

PO

2 (

mm

Hg)

PO

2 (

mm

Hg)

†

†

†

† †

†

†

o Can be relatively non-invasiveo NIRS, spectrophotometry techniques … measures oxyHb (?Mb) in tissue/microvasculo porphyrin phosphorescence technique

… measures microvascular PO2

o skeletal muscle StO2 parallels changes in

human …whole body DO2 during trauma

resuscitation

Microvascular O2 tension/saturationMicrovascular O2 tension/saturation

SUMMARY: tissue/microvascular O2SUMMARY: tissue/microvascular O2

o tissue PO2 (SO2) = useful marker of local

supply- demand balance in non-septic shock or in early …unresuscitated sepsiso raised in resuscitated sepsis - marker of mitochondrial dysfunction o microvascular PO2 - may provide similar info

but …comparative studies neededo no outcome-related PO2-guided studieso research tool at present until better defined in pts

o Low VO2 or poor response in VO2 to challenge

(fluid/dobutamine) = poor prognosis

o Whole body ≠ regional VO2

o How much VO2 is coupled or uncoupled to ATP

…production in shock states?

Whole body/regional O2 consumptionWhole body/regional O2 consumption

Crit Care Med 2000; 28: 2837-42

o mainly measured sublingually

o relevance of tongue to other organ

beds?

… but does correlate with gastric & s/l

PCO2

o prognosticator of outcome in sepsis

MicrocirculationMicrocirculation

o relevance to local tissue O2??

o ? reactive to decreased mitochondrial utilisation c/f

hyperoxia

o +tive correlation between capillary O2 extraction &

degree of regional capillary stopped-flow - i.e.

remaining functionally normal capillaries offload more

O2 to surrounding tissue

o minimal cell death seen in sepsis

o need for automated semi-quantification

technique

o no outcome-related microcirc’n-guided studies

MicrocirculationMicrocirculation

SUMMARY: microcirculationSUMMARY: microcirculation

o interesting research tool for assessing

perfusion

o applicability of tongue to other tissue beds?

o pathophysiological questions - causative or

2°??

o relative infancy - not a routine clinical tool yet

o >90% of VO2 used by mitochondria

o >90% of ATP in most cells generated by ETCo ..thus mitos play a fundamental role in shocko degree of dysfunction in established septic shock relates to poor outcomeo ATP not yet measurable at bedsideo redox status can be used for trend-following

Mitochondrial functionMitochondrial function

NADH fluoroscopy & NIRSNADH fluoroscopy & NIRS

NADH NAD+

oxidisedreduced

Rhee P et al. Near-infrared spectroscopy: Continuous measurement of cytochrome oxidation during hemorrhagic shock. Crit Care Med 1997; 25:166-170

liver

kidney

muscle

stomach

Cyt aa3 (%change from baseline)

CO

DO2

VO2

o cannot yet be quantified in vivoo good for trend-following … … ideally from normal baseline o limited use in patient who’s already critically ill

Mitochondrial redox stateMitochondrial redox state

SUMMARY: mitochondrionSUMMARY: mitochondrion

o .. the ideal organelle to monitor the adequacy of organ perfusiono .. but, at present, no bedside mitochondrial monitor that offers more than trend following

SUMMARY: overallSUMMARY: overall

o shock is not an homogenous condition

o we still lack the perfect bedside tool to assess

adequacy of organ perfusion

o will there ever be one?

o is measuring site representative of other organ

beds?

o should we use an amalgam of technologies?

o tool-directed outcome studies are needed