Intradialytic stunning

The role of systemic circulatory stress in uraemic complications

Intradialytic stunning

The role of systemic circulatory stress in uraemic complications

Chris McIntyreAssociate Professor and Reader in Vascular Medicine

School of Graduate Entry Medicine and Health, University of Nottingham

and

Department of Renal Medicine, Royal Derby Hospital

?

Cardiac risk factors in dialysis patients

Intra-dialytic hypotension

Inter-dialytic weight gain

InflammationFluid/electrolyte

shifts

(arrhythmia risk)

Impaired

CV risk

LVH

LVSD

Vascular calcification

Impaired baroreflex sensitivity

‘Traditional’ risk• Blood pressure

•Cholesterol

• Diabetes•Smoking

•Anaemia

Odudu A, McIntyre CW. J Ren Care 2010

Systemic circulatory stress in HD -Effects of HD on ScVO2

ScVO2 Pre HD 63.5 ±1 3%, post HD 56.4 ± 8% (p=0.04)*

*Harrison L, Selby NM, McIntyre CW. BRS/RA 2010

Repetitive cardiac injury-Hibernation and heart failure

Repetitive Ischaemia andStunning

Functional hibernation

Enzyme induction

DE+FDG+

Metabolic adaptations

Structural hibernation

TIME

Oncogene expression

Cell de-differentiation(Glycogen increase with loss of

contractile proteins etc)

DE-FDG+

Protein Abnormalities

Altered geneexpression/transcription

DE-FDG-

Cell death

Assessing stress response to HD. Regional Wall Motion Analysis

� Semi-automated software

� Wall motion is calculated over 10 regions and expressed as %SF

� RWMA is defined as reduction in SF of >20% between baseline and peak images

� More than 2 RWMAs are significant

HD induced RWMA– prevalence and cTnT levels

cTnT levels and Myocardial Stunning

0.075

0.100

0.125

cT

nT

le

ve

ls (

ng

/mL

)

� The higher the cTnT, the

greater the reduction in SF

≤2 RWMAs >2 RWMAs0.000

0.025

0.050

0.075

Patient groupc

Tn

T l

eve

ls (

ng

/mL

)

Burton JO, Korsheed S, McIntyre CW. Clin J Am Soc Nephrol. 2009 May;4(5):914-20

>2 RWMAs ≤2 RWMAs

43/70(61%)

Troponin release dose not require myocardial necrosis

•Blebs develop on myocyte surface

•Prolonged ischemia � bleb rupture,

necrosis & prolonged troponin release

•Shorter periods of ischemia � bleb

release without rupture, shorter period of

troponin release

Hickman et al. Clinica Chimica Acta 2010

Factors associated with the presence of RWMAs

� Factors associated with development of >2 RWMAs (r2=0.602)

Factor associated with development of myocardial

stunningOR P value

UF volume during HD of 1L 5.1

0.007UF volume during HD of 1.5L 11.6

cTnT 1.26 1.04 – 1.54 0.004

Age 1.07 1.01 – 1.128 0.018

UF volume during HD of 2L 26.2

Max SBP reduction during HD of 10 mmHg 1.8

0.002Max SBP reduction during HD of 20 mmHg 3.3

Max SBP reduction during HD of 30 mmHg 6.0

Burton JO, Korsheed S, McIntyre CW. Clin J Am Soc Nephrol. 2009 May;4(5):914-20

• Hibernation of segments co-localised with stress induced RWMAs

• Reduction in LVEF ~ 10% (absolute)

– At rest

– At peak stress on HD

HD Induced Myocardial Stunning Lead to Myocardial Hibernation and Reduction in Overall Systolic Function

Burton JO, Korsheed S, McIntyre CW. Clin J Am Soc Nephrol. 2009 May;4(5):914-20

Burton JO, Jefferies HJ, McIntyre CW . Clin J Am Soc Nephrol. 2009 Dec;4(12):1925-31

Other significant associations of Dialysis induced myocardial stunning

• Inflammation* – Increased levels of IL-6 and hs-CRP

• Markers of volume status**– Increased TBW (deuterium based)

NT-proBNP – Increased levels of NT-proBNP

• Ventricular arrhythmias***– 12 lead 24 hr Holter (intra and post dialytic monitoring)– complex ventricular arrhythmias (CVA) in 61% of patients

• Elevated LAV****

*Jefferies HJ, McIntyre CW. EDTA 2008

**Jefferies HJ, McIntyre CW. RA/BRS 2008

***Burton JO, Korsheed S, McIntyre CW . Renal Failure 2008

****Haq I, Jefferies HJ, Burton JO, McIntyre CW.ASN 2009

Mortality and time to CV event

Burton JO, Korsheed S, McIntyre CW. Clin J Am Soc Nephrol. 2009 May;4(5):914-20

Intradialytic segmental myocardial perfusion- using cardiac water PET

McIntyre CW. Acute cardiac effects of haemodialysis. Kidney Int 2009

Effect of HD on global and segmental Myocardial Blood Flow

Baseline

On HD- 4hrs

McIntyre CW et al. Clin J Am Soc Nephrol. 2008 Jan;3(1):19-26

Uraemic effects on normal cardiac function

Basal Mid Apical

Segment HD Pts Controls HD Pts Controls Segment HD Pts Controls

Anterior -16±7 -22±2 -15±5 -23±2 Anterior -20±10 -27±2

Antero-septal -12±4 -19±2 -13±4 -21±2 Septal -14±6 -24±2

Infero-septal -6±5 -18±1 -9±6 -20±3 Inferior -15±6 -21±4

Inferior -10±4 -16±2 -11±7 -18±2 Lateral -17±9 -25±3

Postero-Lateral -13±8 -21±2 -9±5 -22±3

Antero-Lateral -15±7 -21±2 -13±6 -24±3

Odudu A, Eldehni MT, McIntyre CW. ISBP 2010

LV Strain studies- 2D Speckle tracing

Pre HD

Post HD

• predisposition to longitudinal axis dysfunction

• predisposition to LV mechanical asynchrony

Hothi D, Rees L, McIntyre CW, Marek T. ASN 2009

Children on dialysis-uraemia without epicardial CAD

Patient Age

(yrs)

Months on

Dialysis

Months

on HD

Cause of ESRF AV

fistula

LV septum

[Z-score]

LV Posterior

wall [Z -score]

1 5.7 4 4 renal dysplasia yes 1.3 1.7

2 17.1 130 89 cystinosis yes 1.6 0.3

3 15.7 43 43 FSGS yes 0.1 1.4

4 15.0 24 4 renal dysplasia yes 0.3 0.2

5 15.7 32 32 FSGS yes 2.6 1.9

6 13.8 7 4 renal dysplasia no 5.9 6.3

7 11.2 41 35 renal dysplasia yes 0.5 -0.6

8 13.6 15 15 FSGS no 0.6 -1.1

9 2.2 7 7 glomerulocystic no 1.5 1.7

10 17.0 12 12 bilateral VUR yes 1.9 1.7

11 7.6 62 62 ARPKD yes 1.0 0.3

12 14.6 23 6 cystic dysplasia yes 2.6 1.2

Hothi D, Rees L, McIntyre CW. Clin J Am Soc Nephrol. 2009 Apr;4(4):790-7

Recurrent HD induced myocardial stunning in children

Mean Segmental Percentage Shortening FractionIn Those Developing RRWM

1

2

3

4

5

Mean

seg

men

tal

SF

(%)

Baseline

0 120 240 15m post0

Time on dialysis (minutes)

120 min Proportion stunning 11/12

Age (years) 12.4(2-17)

UF volume ( L) 1.2±079

Delta BP (mmHg) 25.5± 9

Pre HD LVEF ( %) 55± 8.3

Post HD LVEF ( %) 54.6 ± 7.5

Hothi D, Rees L, McIntyre CW. Clin J Am Soc Nephrol. 2009 Apr;4(4):790-7

PAPP-A in HD patientsCombined study with Finland

• Strongly associated with ACS

and outcomes*

• NO ASSOCIATION WITH HD • NO ASSOCIATION WITH HD

INDUCED ACUTE CARDIAC

INJURY**

*Risto T. Clin Chemistry 2009

**Jefferies HJ, Risto T, Whitforth S, McIntyre CW. ASN 2009

How can aortic compliance induce myocardial ischaemia ?

ECG changes

•3-4 mm ST depression

• at rest and stressed

Myocardial perfusion

Watanabe et al. J Am Coll Cardiol 1993;21:1497-1506

Myocardial perfusion

Microcirculatory disturbance in HD and vascular calcification

120

ACH SNP

p= 0.004

p= 0.01120

ACH SNP

p= 0.004

p= 0.01Pre Iontophoresis

VC+ VC- Normals 0

30

60

90

VC+ VC- Normals VC+ VC- Normals VC+ VC- Normals 0

30

60

90

VC+ VC- Normals VC+ VC- Normals

Sigrist MK, McIntyre CW. Nephron Clin Pract. 2008;108(2):c121-6

Post Iontophoresis

Post Iontophoresis

Myographic ex-vivo arterial assessment

14-05-10

Channel 4 (mN)

-0

5

10

15

kpss

wash out

wash out

wash out

6:31:00 6:32:00 6:33:00 6:34:00 6:35:00 6:36:00 6:37:00 6:38:00 6:39:00 6:40:00 6:41:00 6:42:0084 85 86 87

14/05/2010 18:41:17.842

14-05-10

15

14/05/2010 14:14:35.842B

A

13-05.10 22.00

12

13/05/2010 19:51:08.053

13-05.10 22.00

Channel 5 (mN)

5

10

15

20

23

kpss

27

washout

54:00 56:00 58:001:00:001:02:001:04:001:06:001:08:001:10:001:12:001:14:00

13/05/2010 17:33:38.857A

NON CKD HAEMODIALYSIS

Responses of resistance arteries to (A) KPSS, (B) BK and (C)

Channel 1 (mN)

-0

5

10

13

100nM u4

16

100nM u4

17

100nM u4

19

100 nM U4

20

100nM u4

22

1nM endoth

23

10 uM bk

2:05:00 2:10:00 2:15:00 2:20:00 2:25:00 2:30:00 2:35:00 2:40:00 2:45:00 2:50:00 2:55:00 3:00:00 3:05:00

14-05-10

Channel 1 (mN)

5

10

15

41

1nM ENDOTH

42

1nM endoth

45

1nM endoth

48

1nM endoth

52

1 nM endo

53

1nm endoth

56

100nm u4

58

100 nM U4

60

1nm endoth

66

10 nuM Ach

4:20:00 4:25:00 4:30:00 4:35:00 4:40:00 4:45:00 4:50:00 4:55:00 5:00:00 5:05:00 5:10:00 5:15:00 5:20:00 5:25:00

14/05/2010 16:29:05.842C

Channel 5 (mN)

-0

2

4

6

8

10

12

48

1nM endoth

50

1nM endoth

51

1nM endoth

55

1nM endoth

56

1nM endoth

60

1nM endoth

64

1nM endoth

65

4nM endoth

67

4nM endoth

69

400nM NA

75

10uM BK

30:00 35:00 40:00 45:00 50:00 55:00 1:00:00 1:05:00 1:10:00 1:15:00 1:20:00

13-05.10 22.00

Channel 6 (mN)

-2

0

2

4

6

8

61

100nM U4

63

100nM u4

66

100nM u4

71

400nM NA

79

10uM Ach

50:00 55:00 1:00:00 1:05:00 1:10:00 1:15:00 1:20:00

13/05/2010 20:13:33.053

C

B Figure 14. Differences between artery and vein.

Bushroffa A, Odudu A, Ehehni MT, O’Sullivan S, McIntyre CW. Unpublished data

Reduction in HD induced circulatory stress ameliorates myocardial stunning

10

HD

*

aff

ecte

d L

V

3.00HD**

a) standard dialysis vs. b iofeedback

HD baseline

HD 240min

HD post

RWMA

RWMA

RWMA

Resolution

RWMA

Baseline Peak Recovery

0

5

BFD*

Mean

no

. of

un

aff

ecte

d L

V

regio

ns p

er patient

Baseline Peak Recovery2.00

2.25

2.50

2.75BFD

SF

(MEA

N) (%

)

Baseline Peak Recovery0

5

10

HD 37

HD 35

° °

Mean

no

. o

fun

aff

ecte

d L

V

reg

ion

s p

er p

atien

t

Baseline Peak Recove ry2.2

2.6

3.0

3.4

3.8

4.2HD37

HD35

°°°°

SF

(ME

AN

) (%

)b) standard d ialysis vs. coo l d ialysis

Selby NJ, Burton JO, McIntyre CW. Clin J Am Soc Nephrol 2006N Selby, S Lambie, C Baker, P Camici, C McIntyre. AJKD 2006Selby NJ, Burton JO, McIntyre CW. Clin J Am Soc Nephrol 2006N Selby, S Lambie, C Baker, P Camici, C McIntyre. AJKD 2006

Daily dialysis impact on UF and BP

Weight change Pre-dialysis to Peak stress

-2

0

weig

ht

(kg

)

Change in Systolic BP, Pre-dialysis to Peak stress

20

40

60

SB

P(m

mH

g)

CHD3 CSD HSD HN-6

-4

∆∆ ∆∆ w

eig

ht

(kg

)

CHD3 CSD HSD HN

-80

-60

-40

-20

0

∆∆ ∆∆ S

BP

(mm

Hg

)

Patients fully matched for age, sex, history of IHD and dialysis vintage

Jefferies HJ, Schiller B, Moran J, McIntyre CW. Accepted for publication CJASN 2010

Impact of dialysis schedule-Intradialytic cardiac stunning

CHD3 CSD HSD HN0

20

40

60

80

100

Pe

rce

nta

ge

Num ber of RWM As by D ialysis Regim en

0

1

2

3

4

5

6

Num

ber

of

RW

MA

s

***

***

Weight loss rate vs.Number of stunned segments

1 2 3 4 5 6 7 8

-40

-30

-20

-10

0

10

20

∆∆ ∆∆W

t p

re-p

eak (

mg

/kg

/hr)

- r=-0.409, p=0.0048

CHD3 CSD HSD HNCHD3 CSD HSD HN

0

Jefferies HJ, Schiller B, Moran J, McIntyre CW. Accepted for publication CJASN 2010

Peritoneal dialysis is not associated with myocardial stunning

Limited evidence (<5% of segments during drain/fill cycle)

Studied during drain/fill and at peak ultrafiltrationPatients studied had little structural cardiac disease

Selby NM, McIntyre CW. PDI 2010

baseline Post UFDrain/fill

Endotoxin and heart failure

• Bacterial endotoxin is a lipopolysaccharide (LPS) comprising over 70% of the total bacteria in the human gut

• Stimulus for immune activation in the pro-inflammatory state of congestive heart failure inflammatory state of congestive heart failure (CHF)*

• ET enters the circulation via bacterial translocation from the gut

– bowel oedema – hypoperfusion

• Endotoxinaemia reduces with– Reduction in venous congestion– Selective gut detoxification

*Anker, S.D., et al. Am J Cardiol, 1997

Endotoxaemia in CKD 3- 5D

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

McIntyre CW et al. Clin J Am Soc Nephrol 2010

P < 0.001P < 0.001

Effect of haemodialysis related factors on Endotoxaemia

McIntyre CW et al. Clin J Am Soc Nephrol 2010

Endotoxinaemia and inflammation in daily dialysis patients

30

SDHD NHD

0.05

0.10

0.15

0.20

0.25

EU

/ml_

pre

54

43

CHD3 CSD HSD HN

0

10

20

Pre

-dia

lysis

hs

CR

P (

pg

/ml)

Dialysis hurts hearts- and a whole lot more besides

ENDOTOXIN

Interventional studies are great…..but make sure you’re testing the right one