3cpo the study efficacy of non-invasive ventilation in patients with acute cardiogenic pulmonary...

3CPOThe

Study

Efficacy of Non-invasive Ventilation in Patients with Acute Cardiogenic

Pulmonary Oedema

The 3CPO TrialISRCTN07448447

David NewbyUniversity of Edinburgh, UK

on behalf of the 3CPO Investigators

3CPOThe

Study

• Conflicts of Interest - None

• This project was funded by the NIHR Health Technology Assessment Programme (project number 01/43/01). The views and opinions expressed herein are those of the investigators and do not necessarily reflect those of the Department of Health.

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Declarations

3CPOThe

Study

Acute Cardiogenic Pulmonary Oedema

• Common - 15-20,000 hospital admissions per annum in UK

• Deadly - 15-20% in-hospital mortality

• Costly - 6.5 million hospital days per annum in USA

3CPOThe

Study

Acute Cardiogenic Pulmonary Oedema

• Loop Diuretic Therapy

• Nitrate Therapy

• Oxygen Therapy

• (Opiates)

• Treat Underlying Cause

3CPOThe

Study

Non-invasive VentilationIn Acute Cardiogenic Pulmonary Oedema

“When the household vacuum cleaner is employed, the machine should be run for some minutes first of all to get rid of dust”

Poulton EP, Oxon DM: Left-sided heart failure with pulmonary oedema: Its treatment with the "pulmonary plus pressure machine." Lancet (1936);231:981-983.

3CPOThe

Study

Non-invasive VentilationIn Acute Cardiogenic Pulmonary Oedema

Non-invasive Ventilation:

• Continuous Positive Airway Pressure (CPAP) Ventilation

• Non-invasive Intermittent Positive Pressure Ventilation (NIPPV)

3CPOThe

Study

Kelly et al. Eur Heart J 2002;23:1379-1386

Physiological Improvement with CPAP in Patients with ACPO

Reduced acidosis, respiratory rate and heart rate

3CPOThe

Study

Mortality reducedfrom 22% to 11%

RR 0.53 (95% CI 0.35-0.81)

(Individual GroupSizes of n = 9 to 46)

Masip et al. JAMA 2005;294:3124-3130

Mortality Benefit of CPAP/NIPPV

in Patients with ACPO

3CPOThe

Study

Aims and Hypothesis

In patients with acute cardiogenic pulmonary oedema:

Aims

• Clinical effectiveness of non-invasive ventilation• Comparative effectiveness of CPAP and NIPPV• Safety of non-invasive ventilation

Hypothesis:

• Non-invasive ventilation reduces mortality

3CPOThe

Study

Trial Design

• Multicentre national randomised controlled trial

• Setting: Emergency Department

• Prospective ‘open-label’ trial

• Three treatment interventions in a 1:1:1 randomisation: ‘standard’ oxygen therapy, CPAP or NIPPV

3CPOThe

Study

Inclusion Criteria

Patients older than 16 years of ageSigns and symptoms consistent with acute cardiogenic

pulmonary oedema as the principal clinical complaint: acute dyspnoea and bilateral crackles on chest auscultation

Chest radiograph confirming the diagnosis of acute cardiogenic pulmonary oedema: typical features of interstitial oedema present

Arterial blood gas analysis with a pH of <7.35 (hydrogen ion concentration >45 nmol/L)

Respiratory rate of >20 breaths per minute

3CPOThe

Study

Severely altered consciousness (unconscious or responding to pain only)

Need for immediate lifesaving interventionPatients requiring thrombolysis or percutaneous coronary

intervention for acute ST segment elevation myocardial infarction

A clear alternative primary diagnosisAn inability to provide informed consent at any time

within the trial periodPrevious inclusion in the 3CPO study

Exclusion Criteria

3CPOThe

Study

• Written informed consent • If unable to give written consent:

– witnessed verbal consent – relatives’ assent is obtained. Verbal patient consent

is witnessed in writing by a second individual involved in the patient’s clinical care.

Subsequent written consent is obtained as soon as possible prior to the patient’s data being used in the trial and normally within one week of recruitment.

MREC/02/0/74

Consent

3CPOThe

StudyIntervention

• Randomised (1:1:1) to:

– Standard oxygen therapy (by facial mask)– CPAP (5 cmH2O up titrated to a maximum of 15

cmH2O)– NIPPV (8/4 cmH2O up titrated to a maximum of

20/10 cmH2O)

• Inhaled oxygen of 60%• Attending physicians were encouraged to use nitrate

and diuretic therapy• Opiate therapy was administered at the discretion of

the treating physician

3CPOThe

StudyPower Calculation

Randomisation of 400 patients per group. Intention-to-treat analysis.

Co-primary end-point of mortality between standard oxygen therapy and non-invasive ventilation (CPAP or NIPPV).

• 80% Power at P<0.05, to detect a difference of 6% in mortality assuming a mortality of 15%.

Co-primary end-point of mortality or intubation between CPAP and NIPPV

• 80% Power at P<0.05, to detect a difference of 7% in mortality and intubation rate assuming an event rate of 18%.

3CPOThe

Study

Consort DiagramRecruitedn = 1156

O2 Onlyn = 391

Protocol Violations

n = 14Duplicates

n =10

Treatedn = 367

Patient Withdrawal

n =0

7 Dayn = 367

30 Dayn = 348

Patient Withdrawal

n = 1Refused

Retrospective Consentn = 18

CPAPn = 382

Protocol Violations

n = 18Duplicates

n =18

Treatedn = 346

Patient Withdrawal

n =3

7 Dayn = 343

30 Dayn = 325

Patient Withdrawal

n = 4Refused


NIPPVn = 383

Protocol Violations

n = 10Duplicates

n =17

Treatedn = 356

Patient Withdrawal

n =4

7 Dayn = 352

30 Dayn = 344

Patient Withdrawal

n = 1Refused


3CPOThe

Study

Standard CPAP NIPPV All

Number 367 346 356 1069

Age (years) 78.7 77.6 77.2 77.8

Sex (male) 42% 45% 43% 43%

Sx of MI at Presentation 22% 22% 22% 22%

Ischemic heart disease 63% 65% 60% 63%

Congestive heart failure 45% 42% 47% 44%

Valvular heart disease 12% 11% 9% 11%

COPD 19% 15% 21% 18%

Hypertension 56% 55% 57% 56%

Diabetes Mellitus 30% 30% 33% 31%

Hypercholesterolemia 30% 33% 31% 32%

Current Smoker 16% 19% 19% 18%

PVD 10% 11% 10% 10%

Cerebrovascular disease 18% 17% 16% 17%

Baseline Characteristics

Mean±SD or % (n)No significant differences (P>0.05)

3CPOThe

Study

Baseline CharacteristicsMedications


Anti-platelet Therapy 62% 65% 63% 63%

Anti-coagulant Therapy 14% 11% 13% 13%

ACE Inhibitor/ARB 38% 41% 43% 41%

Aldosterone Antagonist 3% 4% 6% 4%

Diuretic 63% 61% 64% 63%

Beta-Blocker 31% 36% 38% 35%

Calcium Antagonist 19% 18% 23% 20%

Nitrate 22% 26% 26% 24%

Nicorandil 7% 9% 8% 8%

Theophyllines 2% 1% 1% 1%

Oral Steroids 7% 5% 5% 6%

Inhaled Steroids 16% 11% 10% 12%

Bronchodilator Inhalers 19% 13% 17% 16%

% (n)No significant differences (P>0.05)

3CPOThe

Study

Immediate TherapeuticInterventions


Nitrate Therapy 93% 88% 91% 90%

Diuretic Therapy 90% 89% 89% 89%

Opiate Therapy 3% 5% 4% 4%

Inspired Oxygen (L/min) 12±4 13±4 12±4 12±4

Ventilation Pressure (cmH2O)

- 10±4 14±5/7±2 -

No significant differences (P>0.05) except ventilation pressures Mean±SD or %

3CPOThe

Study Trial treatment

Standard CPAP NIPPV P-value

Treatment allocated 365 342 351

Started allocated treatment

365 (100%) 336 (98.2%) 341 (97.2%) 0.07

Completed allocated treatment

298 (83.2%) 284 (84.5%) 265 (77.7%) 0.016

Not tolerated 1 (0.3%) 18 (5.4%) 30 (8.8%) <0.001

Worsening ABGs 26 (7.1%) 10 (3.0%) 15 (4.4%) 0.027

Respiratory distress 31 (8.5%) 5 (1.5%) 12 (3.5%) <0.001

Other reason 17 (4.6%) 24 (7.1%) 25 (7.3%) 0.152

Changed to standard 3 (0.8%) 32 (9.5%) 51 (15.0%)

Changed to CPAP 43 (11.8%) 1 (0.3%) 12 (3.5%)

N (%)

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Study

Tolerability andSide-effects


Vomiting 6 (1.7%) 6 (1.8%) 8 (2.3%) 0.808

Aspiration 0 0 1 (0.3%) 0.367

Hypotension 46 (13.1%) 36 (10.9%)

37 (10.8%) 0.554

Arrhythmia 23 (6.6%) 12 (3.6%) 25 (7.3%) 0.097

Pneumothorax 0 0 1 (0.3%) 0.367

Increasing Respiratory Distress

35 (9.9%) 17 (5.1%) 20 (5.8%) 0.028

Cardiac Arrest 16 (4.5%) 6 (1.8%) 10 (2.9%) 0.118

Other 23 (6.6%) 18 (5.5%) 17 (5.0%) 0.661

% (n)

3CPOThe

Study

Tolerability andSide-effects of

Non-Invasive Ventilation

CPAP NIPPV

Facial skin necrosis 0 0 1.0

Facial discomfort 14 (4.7%) 15 (4.9%) 0.929

Increased breathing discomfort

11 (3.7%) 16 (5.2%) 0.370

Other side effect 16 (5.4%) 19 (6.2%) 0.659

% (n)

3CPOThe

Study


Pulse rate (/min) 114±24 113±21 112±22 113±22

Systolic BP (mmHg) 161±38 162±35 161±37 162±37

Diastolic BP (mmHg) 87±25 89±23 87±24 88±24

Respiratory Rate (/min) 33±7 32±7 32±7 32±7

Oxygen Saturation (%) 91±8 90±8 90±8 90±8

Arterial pH 7.22±0.08 7.21±0.09 7.21±0.09 7.22±0.09

Arterial pO2 (kPa) 13.1±7.6 13.5±7.7 13.4±8.6 13.3±8.0

Arterial pCO2 (kPa) 7.6±2.5 7.5±1.9 7.7±2.3 7.6±2.2

Bicarbonate (mmol/L) 21±4 21±4 21±5 21±4

GCS verbal=5 90% 88% 91% 89%

GCS eye opening=4 91% 86% 90% 89%

GCS motor=6 96% 97% 98% 97%

Baseline CharacteristicsPhysiological Variables

Mean±SDNo significant differences (P>0.05)

3CPOThe

Study

Physiological Response to Intervention

One Hour Physiology

Standard CPAP or NIPPV

P Value

(t-test)

Pulse rate (/min) 102±23 96±22 <0.001

Systolic BP (mmHg) 128±30 124±27 0.073

Diastolic BP (mmHg) 65±20 66±18 0.390

Respiratory Rate (/min) 26±6 25±6 0.023

Oxygen Saturation (%) 94±6 93±6 0.044

Arterial pH 7.30±0.08 7.32±0.08 <0.001

Arterial pO2 (kPa) 14.1±8.5 13.0 ±9.0 0.074

Arterial pCO2 (kPa) 6.7±2.5 6.2±1.9 <0.001

Bicarbonate (mmol/L) 22±8 22±6 0.934

Mean±SD

3CPOThe

Study

Physiological Response to Intervention

One Hour Physiology

CPAP NIPPV P Value

(t-test)

Pulse rate (/min) 96±20 97±24 0.763

Systolic BP (mmHg) 124±27 124±28 0.915

Diastolic BP (mmHg) 66±19 66±18 0.671

Respiratory Rate (/min) 25±7 24±6 0.372

Oxygen Saturation (%) 94±6 93±7 0.066

Arterial pH 7.33±0.07 7.32±0.08 0.143

Arterial pO2 (kPa) 12.4±7.8 13.6±9.9 0.079

Arterial pCO2 (kPa) 6.0±1.6 6.3±2.2 0.107

Bicarbonate (mmol/L) 23±7 22±5 0.110

Mean±SD

3CPOThe

Study

Primary OutcomeAny NIV v standard

Mortality

Standard Therapy

Non-Invasive

Ventilation

Odds Ratio 95% Confidence

Intervals

P Value

7-Day 9.8% 9.5% 0.97 0.63 to 1.48 0.869

30-Day 16.7% 15.4% 0.93 0.65 to 1.32 0.685

3CPOThe

Study

Primary Outcome: Mortality Standard Oxygen Therapy

versus Non-invasive Ventilation

1.0

0.9

0.8

0 10 20 30Days

CumulativeSurvival

StandardOxygen Therapy

Non-invasiveVentilation

P=0.685

3CPOThe

Study

Primary OutcomeCPAP v NIPPV

Mortality

CPAP NIPPV Odds Ratio 95% Confidence Intervals

P Value

7-Day

Mortality

9.6% 9.4% 0.97 0.59 to 1.61 0.912

7-Day

Mortality/Intubation

11.7% 11.1% 0.94 0.59 to 1.51 0.806

30-Day

Mortality

15.4% 15.4% 0.99 0.65 to 1.51 0.976

3CPOThe

StudyHospital stay


Admitted to intensive Care

8.8% 9.1% 6.6% 0.411

Admitted to high-dependency Care

7.7% 10.3% 10.9% 0.301

Admitted to coronary Care

38.1% 43.7% 40.9% 0.337

Median length of hospital stay in days ( IQR)

8 (5-13) 9 (5-16) 9 (5-16) 0.313

No significant differences (P>0.05)

3CPOThe

Study

In patients with acute cardiogenic pulmonary oedema, non-invasive ventilation:

• Produces more rapid resolution of metabolic abnormalities and respiratory distress

• Has no major effect on 7-day or 30-day mortality

• Is beneficial irrespective of the mode (CPAP or NIPPV) of delivery

CONCLUSIONS

3cpo the study efficacy of non-invasive ventilation in patients with acute cardiogenic pulmonary...

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