Adjunct Approaches to the Care of the PARDS Patient. Doug Willson, MD Children s Hospital of Richmond April 21, 2015

Transcription

1 Adjunct Approaches to the Care of the PARDS Patient Doug Willson, MD Children s Hospital of Richmond April 21, 2015

2 Disclosures! I am a consultant for Discovery Laboratories! No other conflicts to disclose

3 Adjunct Treatments The most important adjunct treatment is more of a philosophy we now understand that it is not necessary to destroy the lung to save the patient -- baby lung concept " low Vt ventilation --permissive hypercarbia --permissive hypoxia

4 Adjunctive Therapy SUPPORTIVE THERAPY

5 Pop Quiz What is the most common avoidable cause of morbidity and mortality in PARDS? 1. Accidental extubation 2. Fluid overload 3. Pneumothorax 4. Nosocomial infection

6 Avoidance of Nosocomial Infection!! Hospital-acquired infections have a higher mortality than any of the top 10 leading causes of death in the U.S. (and rank 8 th as cause of death in U.S.)! VAP, for example, increases mortality 4 fold in adult intensive care! Bloodstream infections are equally frightening

7 Incidence rates and distribution of pathogens most commonly isolated from monomicrobial nosocomial bloodstream infections (BSIs) and associated crude mortality rates for all patients, patients in intensive care units (ICU), and patients in non-icu wards. Hilmar Wisplinghoff et al. Clin Infect Dis. 2004;39:

8 Wash your hands!!!!!!!

9 Nutrition! Inability to achieve 1/3 of energy needs in first 10 days clearly associated with mortality*! A higher % of goal enteral nutrition intake associated with lower mortality*! EDEN trial in adults, however, showed no benefit to trophic vs. full enteral feedings in first 6 days of ARDS (or to the specific supplementation with fish oil, etc.)** *Mehta, CCM 2012 **Rice, JAMA 2012

10 % Goal Nutrition in First 10 days PICU Figure 1. Daily mean cumuladve energy intake (as percentage of prescribed goal) for the cohort. EN, enteral nutridon; PN, parenteral nutridon; PICU, pediatric intensive care unit. Nutri&onal prac&ces and their rela&onship to clinical outcomes in cri&cally ill children- An interna&onal mul&center cohort study*. Mehta, Nilesh; Bechard, Lori; MEd, RD; Cahill, Naomi; RD, MSc; Wang, Miao; Day, Andrew; Duggan, Christopher; MD, MPH; Heyland, Daren; MD, MSc CriDcal Care Medicine. 40(7): , July DOI: /CCM.0b013e31824e18a8 2

11 Fluid Management! The dry lung is the happy lung!! Initial resuscitation is vital (Rivers, et al), but fluid restriction after resuscitation to avoid fluid overload shown by FACTT trial to decrease days on ventilator! In my experience this is one of the most commonly overlooked aspects of management

12 Fluid Protocol (CARDS study)

13 Fluid Management Relationship of cumulative fluid balance to mortality Relationship of cumulative fluid balance to ventilatorfree days (Willson et al. 2014)

14 Fluid Management! Fluid is a drug like any other and has a therapeutic range and a toxicity! Positive pressure ventilation leads to fluid accumulation (decreased venous return)! Should aim toward even or negative fluid balance after stabilization

15 Sedation: Pop Quiz #2 Which of the following medications have been associated with tolerance and withdrawal in children? 1. Midazolam (Versed) 2. Dexmedetomidine (Precedex) 3. Hydromorphone (Dilaudid) 4. Pentobarbital 5. Fentanyl 6. Lorazepam 7. All of the above

16 Sedation/Analgesia! Adequate sedation/analgesia is necessary to prevent adverse consequences in kids (i.e., accidental extubation)! Over-sedation is the most common reason for failure to wean from mechanical ventilation! Tolerance and it s corollary, withdrawal, are common problems in the PICU and prolong hospital stay.! Unfortunately RESTORE study did not show shortened duration of mechanical ventilation with protocolized sedation

17 Sedation: The Benefit of a Protocol Median daily narcotic dose across the 7 CPCCRN sites. Only site with arrow used a protocol for sedation administration

18 Supportive Care Avoidance of infection, appropriate fluid management, good nutrition, and judicious sedation are likely as important (if not more important) than any specific therapy for PARDS!

19 Adjunct Care! Specific adjunctive therapy! Nitric oxide! Prone positioning! Surfactant! Steroids! ECMO

20 Pop Quiz #3 Inhaled nitric oxide 1. Is expensive 2. Generally immediately improves oxygenation 3. Has been associated with renal dysfunction 4. Improves distribution of perfusion relative to ventilation in the lung 5. All of the above 6. Only 1, 2, 4

21 Nitric oxide! Vasodilates where the gas goes"improved distribution of perfusion relative to ventilation! Invariably initially improves PaO2 but not sustained! Expensive Just ($140/hr) say no!! Oxygenation can worsen when discontinued because of inhibition of endogenous NO! No demonstrated improvement in duration of ventilation, LOS, or mortality! Effective treatment in pulmonary hypertension (although pulmonary hypertension is part of PARDS)

22 Nitric Oxide: 9 studies Fig 2 Effect of nitric oxide on mortality. Weight is the relative contribution of each study to the overall estimate of treatment effect on a log scale assuming a random effects model. Two trials with 50% of control patients crossing over to nitric oxide also reported mortality data. w2w6 Inclusion of these trials did not alter summary mortality estimate (risk ratio 1.09, 0.94 to 1.27 (Adhikari, BMJ 2007)

23 Dobyns J Peds 1999; 134: Dobyns study showed no longer-term benefit from NO Improved oxygenation with NO 10 ppm vs. placebo in 108 children with acute hypoxemic respiratory failure Proportion of subjects with response to NO over 72 hours (p=n.s.)

24 Nitric Oxide Just say no!

25 Prone Positioning

26 Prone Positioning! Recruitment maneuver! Like NO, transiently improves PaO2! No longer-term benefit in initial studies (Gattinoni, Curley)! Few side effects, easily accomplished in small children

27 Prone Positioning in Children Improvement seen with position change (64% of position changes resulted in a 20 mmhg or greater increase in PaO2) but no longer term benefit Curley JAMA 2005 No significant differences were found between the 2 groups (p=.91)

28 Kaplan Meier Plot of the Probability of Survival fromrandomization to Day 90. Prone Positioning in Severe ARDS Guerin C, et al. NEJM 2013 RCT of prone positioning (16 hrs) vs. supine in 466 subjects with severe ARDS (P/F ratio < 150). 90 day mortality 23.6% in prone vs. 41% in supine group. No significant adverse effects of proning Guérin C et al. N Engl J Med 2013;368:

29 Prone Positioning! Dependent atelectasis is usual in ARDS! Proning recruits these areas " improved oxygenation! Really no down side, particularly in kids! Despite absence of evidence for longerterm efficacy, would recommend

30 Steriods! Older studies--no benefit in acute ARDS! Newer study (Meduri)--benefit in chronic stage of ARDS! Concept of CIRCI (critical illness related corticotropin insufficiency)! Newer still study (ARDSnet)--not beneficial in chronic stage of ARDS! Newest studies--may be beneficial in acute ARDS, chronic ARDS, or not!

31 Pop Quiz: Corticosteroids Corticosteroids have been associated with all but one of the following side effects: 1. Cataracts 2. Hypertension 3. Calcium wastage 4. Psychosis 5. Abdominal stria 6. Sleep disturbances 7. Weight gain 8. Osteoporosis 9. Avascular necrosis 10. Seizures 11. Depression 12. Suppression of the HPA axis 13. Myopathy 14. Acne

32 Probability of Survival and the Proportion of Patients with Persistent ARDS Who Became Able to Breathe without Assistance during the First 180 Days after Randomization. Steroids in ARDS Extubated sooner but more reintubated (Meduri argues they had rebound from withdrawal of steroids) The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. N Engl J Med 2006;354:

33 Changes in Inflammation and LIS with Steroids vs. Placebo! Rx: Methylprednisolone 1mg/kg/d up to 28 days vs. placebo (adults)! 2:1 randomization w/ crossover! Primary outcome 1 pt. change in LIS and/or extubation Changes in C-reactive protein and LIS over 7 days for patients randomized to methyl-prednisolone (n = 63) and placebo (n = 28) Meduri, G. U. et al. Chest 2007;131:

34 Survival Curves! VFDs 16.5 vs. 8.7 (p=0.001)! ICU Survivors 79% vs. 57% (p=003) N=72 N=91 but... small study cross-over design no vent or weaning protocol control group had higher co-morbidities Meduri, G. U. et al. Chest 2007;131:

35 Steroids No studies in kids but steroids were used in 40% of patients in one Indian study and 60% in a German study

36 Surfactant! RCTs in adults have been disappointing (Anzueto, Gregory, Spragg)! RCTs in children more hopeful (Willson, Luchetti)! No currently active studies in ARDS

37 Alveolar side Surfactant Dysfunction in Acute Lung Injury Direct Injury Acute Lung Injury Indirect Injury Vascular side Alveolar-capillary integrity Alveolar metabolism of surfactant Type II Pneumatocytes Inflammation Increased permeability Pulmonary Edema Abnormal Surfactant Aggregate Forms Altered Surfactant Synthesis Secretion Composition Surfactant Dysfunction Granulocyte Migration Macrophage Activation SP-A Depletion Inflammatory mediators Oxidants, Proteases Lung mechanics and gas exchange abnormalities FRC Compliance Shunt

38 Randomized Infasurf Trial Mid-Atlantic Pediatric Critical Care Network: CCM, 1999 # 42 children with acute hypoxemic respiratory failure # Prospective, randomized, but not blinded # Two doses 80 ml/m 2 12 hours apart # Ventilator protocol

39 Infasurf Study Calfactant (n=77) Placebo (n=75) P Value Mortality Died (in hospital) 15 (19%) 27 (36%) 0.03 Died w/o extubation 12 (16%) 24 (32%) 0.02 Failed CMV* 13 (21%) 26 (42%) 0.02 ECMO 3 3 Use of Nitric Oxide 9 10 HFOV after entry 7 15 Secondary Outcomes PICU LOS 15.2 ± ± Hospital LOS 26.8 ± ± Days O2 Therapy 17.3 ± ± Hospital Charges# $205 ± 220 $213 ± *Conventional mechanical ventilation--note that some patients had > one non-conventional therapy # Charges in thousands, USD Willson JAMA 2005

40 CARDS Study! No change in oxygenation with surfactant! No difference in VFDs, mortality, etc. in either the adult or pediatric arm! Differences in drug and recruitment may account for lack of response

41 Exogenous surfactant The jury is still out...

42 ECMO! When all else fails...! Use for respiratory failure has leveled off in the U.S. (ELSO statistics), although increasingly used cardiac and for E-CPR! New technology (smaller pumps, better cannula, more portable) is likely to lower the threshold for use.

43 Peds Respiratory Cases (ELSO) Annual Runs No. Cases Cumulative Cumulative Runs

44 CESAR Trial Murray score > 3 ph < 7.2 reversible ARDS 63% 47% Note that ECMO was veno-venous! Figure 2 Kaplan-Meier survival estimates ECMO=extracorporeal membrane oxygenation. *Patients were randomly allocated to consideration for treatment by ECMO, but did not necessarily receive this treatment. The Lancet, Volume 374, Issue 9698, 2009,

45 ECMO for Pediatric Respiratory Failure

46 ECMO Questions! Should ECMO always be the last resort?! Should passive ECCOR be considered like lung dialysis and used preventively?! How (and in whom) are we to study these issues?

47 Pop Quiz Mortality is decreasing in PARDS 1. True 2. False

48 Declining mortality in PARDS

49 Adjunctive Rx for PARDS Conclusions! Blood gases don t have to be normal! Supportive care is critical! Surfactant and nitric oxide probably not helpful and both are expensive! Prone positioning is free, likely not harmful, and worth trying!?steroids for chronic ARDS! To paraphrase Bogart we ll always have ECMO

50 Future Directions It s difficult to make predictions, particularly about the future... Yogi Berra