Renal ICM updates- what’s new?

J PlumbOct 2014

Scouring the literature

• ‘Dose’ and ‘Dose’ in Sepsis 3 big papers from 2008, 2009 & 2013

• Review of UK ICM Practice is insightful 2013 (Jones)

• Biomarkers- 2014• Optimal timing- a few papers on this• Anticoagulation (Phil)• Modes (SLED etc.)- Great review from

‘uptodate’• CIN/CI-AKI

‘Dose’‘Dose in sepsis and HVHF

Original Article Intensity of Renal Support in Critically Ill Patients with Acute Kidney Injury

VA/NIH Acute Renal Failure Trial Network

N Engl J Med Volume 359(1):7-20 July 3, 2008

Original Article Intensity of Continuous Renal-Replacement Therapy in Critically Ill Patients

The RENAL Replacement Therapy Study Investigators

N Engl J Med Volume 361(17):1627-1638 October 22, 2009

Not new but 2 studies that you should know about

VA/NIH ATN Study 2008

• Multi-centre randomised parallel group study (27 centres)

• 1124 patients with AKI and failure of ≥ 1 non-renal organ system or sepsis

• Randomised to receive intensive (n=563) or less intensive (n=561) therapy

• Haemodynamically stable patients received iHD

• Unstable patients received CVVHDF or SLED• Primary endpoint – 60 day mortality

• Intensive therapy group– IHD or SLED 6 x per week or CVVHDF at

35mL/kg/hr

• Less intensive therapy group– IHD or SLED 3 x per week or CVVHDF at

20ml/kg/hr

• Baseline characteristics of the 2 groups were similar

Results • No significant difference between the 2

groups in:– Rate of cause of death from any cause at 60

days• Intensive group 53.6%• Less intensive group 51.5%

– Duration of RRT– Rate of recovery or renal function– Rate of recovery of non-renal organ function

• Limitations:– Excluded patients with CKD– No information given about timing of

initiation of therapy or fluid balance

Why was the RENAL study done?

• The optimal approach to renal-replacement therapy, as well as the optimal intensity and timing of such therapy, in critically ill patients remains unclear

• Ronco’s early paper(2000) had suggested improved survival with increased intensity. However, subsequent single-centre studies have had conflicting results

Important relevance to UK practice• They comment on the VA/NIH ATN • Note RENAL ANZCA• VA/NIH ATN USA• Different practice• This design reflects clinical practice in the United

States and elsewhere but makes it difficult to carry out a formal comparison of treatment intensities that would be independent of the particular treatment approach. We conducted a randomized, controlled study to test the hypothesis that increasing the intensity of continuous renal-replacement therapy would reduce mortality at 90 days.

RENAL Study 2009

• Multicentre randomised trial– 34 centres in Australia and New Zealand

• 1508 patients over a 3 year period• Compared 2 levels of intensity of CRRT on the

90 day mortality of critically ill patients with AKI

• Randomised to receive– CVVHDF at 40mL/kg/hr – CVVHDF at 25mL/kg/hr

• Similar baseline characteristics between the 2 groups

• Received the CRRT for a similar length of time

Results • 90 days after randomisation

– 322 deaths in higher intensity treatment group– 332 deaths in the lower intensity treatment group– p = 0.99

• No significant difference in the number of survivors in each group that remained RRT-dependent at 90 days– 27/399 survivors in the higher intensity group– 18/411 survivors in the lower intensity group– p = 0.14

• Hypophosphataemia more common in the higher intensity treatment group – 65% vs 54% (p< 0.01)

Of note..

• In all previous studies, delivered doses were less than 85% of the prescribed doses.

• Why was that?• The difference between the prescribed dose and

the delivered dose highlights the risk of overestimating the effective delivery of therapy and the need to improve operational measures in continuous renal-replacement therapy. Specifically, basing the delivered dose on effluent volume most likely overestimates true solute clearance. Future trials should measure solute clearance rather than simply relying on effluent volume.

Should it have changed our practice?

• In countries where continuous renal-replacement therapy is now the preferred form of renal-replacement therapy in the ICU, our study has implications for clinical practice. We found that a prescribed treatment intensity that exceeds 25 ml of effluent flow per kilogram per hour adds no significant benefit and exposes patients to the risk of hypophosphatemia.

• There has been a widespread increase in the use of higher-intensity continuous renal-replacement therapy, and our findings indicate that such practice is not justified.

More on this

• Specifically to sepsis

Cytokines and stuff

• Sepsis and high volume haemofiltration (HVHF)

• Inflammatory mediators such as TNF and IL6 fall into the category of ‘middle molecular weight’ molecules and it has been shown that it is possible to remove them by renal replacement therapies, particularly convective therapies

• This led to interest in whether this property can be used as an adjunct in the treatment of septic shock.

• Sepsis- releases ‘nasties’ RRT mops them all up?

• Concept of HVHF came out of the high volume of ‘nasties’ effluent rate 50-70mls/kg/hr

IVOIRE study 2013 ICM

In the IVOIRE trial, there was no evidence that HVHF at 70 mL/kg/h, when compared with contemporary SVHF at 35 mL/kg/h, leads to a reduction of 28-day mortality or contributes to early improvements in haemodynamic profile or organ function. HVHF, as applied in this trial, cannot be recommended for treatment of septic shock complicated by AKI.

• Most intensivists would agree it is prudent to start RRT sooner in critically ill patients rather than wait for “absolute” indications to develop

• Most ICUs have a protocol to prescribe an effluent rate of 30-35mL/Kg/hr (used as a proxy for treatment dose) on the basis that most patients will actually get around 25mls/kg/hr

What was the theory?

• Along with having the potential to modulate the immune system response to sepsis by removal of toxins and other inflammatory mediators that contribute to organ injury and dysfunction

• Indeed, experimental studies have shown HVHF can improve myocardial performance and systemic haemodynamics while also removing inflammatory cytokines

Problems with the study• The evidence was poor so it was a god idea to perform

the trial• But it was not adequately powered!

• Unfortunately, the IVOIRE study was stopped prematurely on the basis of the trial steering committee’s recommendation with support from the DSMC, primarily because of a lower than anticipated primary endpoint event rate, slower than anticipated participant accrual and for reasons related to limited resources. As a consequence, the trial had insufficient statistical power to detect a 15 % absolute reduction (25 % relative reduction) in 28-day mortality.

Conclusions

The findings of these studies, together with the adverse effects of HVHF (excessive clearance of electrolytes, drugs and nutrients as well as cost -financial and nursing time) mean that HVHF cannot be recommended as standard practice for patients with septic shock and AKI.

Have people actually measured the cytokines etc?

• Yes and they still are • 2002, Bellomo et al- studied if early

CRRT affected humoral mediators, • What did they measure? complement

fractions C3a and C5a, interleukins 6, 8, and 10, and tumor necrosis factor alpha

• PATIENTS: Twenty-four patients with early septic shock or septic organ dysfunction.

• INTERVENTIONS: Random allocation to receive 48 hrs of isovolemic CVVH at 2 L/hr of fluid exchange or no

• CONCLUSIONS: Early use of CVVH at 2 L/hr did not reduce the circulating concentrations of several cytokines and anaphylatoxins associated with septic shock, or the organ dysfunction that followed severe sepsis. CVVH using current technology cannot be recommended as an adjunct to the treatment of septic shock unless severe acute renal failure is present.

Haemofiltration for sepsis?

• Another trial was discontinued after an interim analysis showed more frequent and more severe organ failure in the hemofiltration group (Payen et al 2009)

• 2013-……..

Recent papers on this?

• 2013 Jul 23. (Servillo G et al)• “Immunomodulatory effect of

continuous venovenous hemofiltration during sepsis: preliminary data.”

• Small study looking at cytokines etc.

• “We suggest that an immunomodulatory effect might exist during CVVH”

Conclusions

Personally I think that it does warrant more study, particularly into the differences that different filter media may or may not have? Perhaps more bench stuff first??

Review of UK ICM Practice 2013

Review of UK ICM Practice 2013

• Nephrol Dial Transplant (2013) 28: 1186–1190 doi: 10.1093/ndt/gft015

• This is worth reading• Jones et al

What was this paper about?

In depth telephone interviews with UK ICUs about what they do and why they do it

Based on the following premise

“Despite its widespread use, there are several controversies about the optimal way that RRT should be delivered, particularly with respect to modality (convective versus diffusive methods), timing of initiation and discontinuation and prescribed dose.”

What did they find out?

• 72% response rate! (This is pretty good!)

• In over 40% of the units, a nephrologist is never or only rarely consulted, although 58% of ICUs have a renal service based on the same hospital site or within the same NHS Trust

Jones SL, Devonald MAJ. How Acute Kidney Injury is investigated and managed in UK Intensive Care Units – a survey of current practice. Accepted for publication

Jones SL, Devonald MAJ. How Acute Kidney Injury is investigated and managed in UK Intensive Care Units – a survey of current practice. Accepted for publication

Jones SL, Devonald MAJ. How Acute Kidney Injury is investigated and managed in UK Intensive Care Units – a survey of current practice. Accepted for publication

Conclusions

“RRT is a life-sustaining intervention providing a bridge to renal recovery in many survivors, yet key aspects of its optimal delivery remain unclear. A lack of international consensus remains in how these patients should be managed. The choice of RRT modality, dose, initiation and discontinuation criteria are likely to remain variable and controversial until adequately designed randomized controlled trials provide convincing evidence. “

Biomarkers

• Future work: There is much interest in kidney biomarkers – something that will not only give an indication of function but also indicates when injury has occurred – and when recovery is happening. Potential biomarkers indicating renal injury include kidney injury molecule-1 (KIMI-1), neutrophil gelatinase associated lipocalin (NGAL), interleukin 18 and urine cystatin C.

Good review article 2014

• Blood Purif 2014;37:271–285 DOI: 10.1159/000360689 (RONCO et l)

• Published online: July 3, 2014 • Neutrophil Gelatinase-Associated

Lipocalin: Ready for Routine Clinical Use?An International Perspective

• It is LONG

Main points NGAL

• It has a lot of promise• It is a marker of injury rather than

function per se• Interesting ongoing study in major

burns looking at balance of NGAL and BNP.

Optimal timing• Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2013

Jul;25(7):415-9. doi: 10.3760/cma.j.issn.2095-4352.2013.07.012.

• Influence of time of initiation of continuous renal replacement therapy on prognosis of critically ill patients with acute kidney injury.

• “Our results indicated that the time of initiation of CRRT by AKIN classification has no effect on the 28-, 90-, 180-day survival rate, ICU survival rate and outcome of renal function in survivors of critically ill patients with AKI. Improving CRRT dose may improve 28-day survival rate.”

But

• Small retrospective study• Poor evidence base again another

area that likely needs further research

• What do we currently do- 2013 paper above did ask this

Modes• Italian article I loved the title: “SLED v CRRT: the

choice between a Rolls and a Ferrari?”

• SLED combines excellent detoxification and good cardiovascular tolerability for even severely ill patients in the ICU. SLED also provides good treatment time flexibility at lower costs than CRRT with the advantage that existing dialysis systems can be used. In conclusion, SLED represents an alternative to CRRT, enabling optimal treatment of complex critically ill patients. It can be considered a key treatment modality for patients on ICU, giving nephrologists and ICU physicians the opportunity for pooling their twin areas of expertise.

Are we slow to uptake SLEDD?

• What’s the downside to what we do?• Initial costs of specialized CRRT machinery• Subsequent running costs of specialized CRRT lines and

filters• Increased costs from reconstituted or commercial fluid

for dialysate or filtrate replacement• Procedural complexities resulting in increased workload

for already busy intensive care unit (ICU) nurses• Frequent unexpected interruptions to CRRT because of

out-of-unit diagnostic and therapeutic procedures, leading to reduction in dialysis dose from "down time"

• Expense and inconvenience from unexpected extracorporeal circuitry replacement

Terminology!!

• The umbrella term "prolonged (daily) intermittent renal replacement therapy" (PIRRT), although the term "hybrid therapy" is also acceptable. Other terms are used in the literature to refer to subsets of PIRRT, and include "sustained low efficiency (daily) dialysis" (SLEDD), "sustained low efficiency (daily) diafiltration" (SLEDD-f), "extended daily dialysis" (EDD), "slow continuous dialysis" (SCD), "go slow dialysis", and "accelerated venovenous hemofiltration" (AVVH).

Why bother?

• To combine the therapeutic advantages of CRRT with the logisitc/cost advantages of iHD

• Solute and fluid removal are slower than conventional iHD, but faster than conventional CRRT. This allows for scheduled "down time" without compromise in dialysis dose.

• A 2 year single centre experience of PIRRT versus CRRT suggested no difference in cardiovascular stability between modalities

• The most rigorous assessment of cardiovascular stability during hybrid treatments comes from a randomized controlled trial of PIRRT versus CRRT

• 39 critically ill patients were randomly assigned to either arm, achieving total ultrafiltration of 3 L over 12 hours and 3.3 L over 24 hours during the hybrid treatment and CRRT, respectively.

• There was no significant difference in inotrope dose or number, although there was an insignificant trend to lower blood pressure and cardiac output, and higher peripheral vascular resistance. This trend was not reflected in outcomes, and any associated cardiovascular instability that might exist is likely to be of little clinical significance.

• Drug clearance — Drug clearance can be considerable with PIRRT and intermediate between that iHD and CRRT

• ‘Although not yet supported by objective data, our opinion is that PIRRT will become the dominant acute renal replacement therapy over the next 5 to 10 years.”

CI-AKI

• Covered in another talk (If we have time)

Thanks for your attention