Pulmonary and Critical Care

Critical Care

RIVERS trial: Goal-directed therapy for septic shock

Article Name: Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa010307

Journal and year of publication: NEJM, 2001

Trial Design: Randomized clinical trial

Population: 263 patients
Key inclusion criteria:
– Fulfilling 2 out of 4 criteria for SIRS
– SBP no higher than 90 mm Hg OR
– Blood lactate 4 mmol per liter or more
Key exclusion criteria:
– Acute pulmonary edema
– Active gastrointestinal hemorrhage
– Immunosuppression

Intervention Studied: Early goal-directed therapy

Control: Standard therapy

Outcomes:
– In-hospital mortality: Early goal-directed therapy: 30.5% vs Standard therapy: 46.5% (P=0.009)
– In addition, Early goal-directed therapy showed better results with regards to lactate improvement, oxygen saturation, and pH improvement

The authors concluded that “Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.”

Citation: _{Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001 Nov 8;345(19):1368-77. doi: 10.1056/NEJMoa010307. PMID: 11794169.}

Note: While the RIVERS trial influenced the sepsis guidelines, the results of the trial were called into question as it was unclear which part of the EGDT protocols contributed to improved survival and after following trials, such as the PROCESS trial below, found that EGDT protocols did not improve survival compared to routine clinical care. However, the trial is still discussed in academic centers and some of its protocols, such as maintaining MAP > 65, CVP 8 -12 mmHg, and monitoring urine output, are used regularly in clinical practice.

PROCESS trial: Protocol-based therapy for septic shock

Article Name: A Randomized Trial of Protocol-Based Care for Early Septic Shock

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1401602

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 1,341 patients
Key inclusion criteria:
– Fulfilling 2 out of 4 criteria for SIRS
– SBP no higher than 90 mm Hg OR
– Blood lactate 4 mmol per liter or more
Key exclusion criteria:
– Acute pulmonary edema
– Active gastrointestinal hemorrhage
– Burn or trauma
– CD4 count <50/mm2

Intervention Studied:
1) Protocol-based EGDT
2) Protocol-based standard therapy

Control:
3) Usual care

Outcomes:
-Deaths (by 60 days): Protocol-based EGDT: 21.0% of patients vs Protocol-based standard therapy: 18.2% of patients vs Usual care: 18.9% of patients (not statistically significant)
– No significant difference in the need for organ support

The authors concluded that ” In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes.”

Citation: _{ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, Weissfeld LA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18. PMID: 24635773; PMCID: PMC4101700.}

SEPSISPAM trial: Blood pressure goal for septic shock

Article Name: High versus Low Blood-Pressure Target in Patients with Septic Shock

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1312173

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 776 patients
Key inclusion criteria:
– Septic shock refractory to fluid resuscitation and required vasopressors
Key exclusion criteria:

Intervention Studied: Resuscitation with MAP target of (80 to 85 mm Hg) (high-target group)

Control: Resuscitation with MAP target of (65 to 70 mm Hg) (low-target group)

Outcomes:
– There was no significant difference between groups in the following areas: mortality at 28 days and at 90 days or adverse events

The authors concluded that “Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days.”

Citation: _{Asfar P, Meziani F, Hamel JF, Grelon F, Megarbane B, Anguel N, Mira JP, Dequin PF, Gergaud S, Weiss N, Legay F, Le Tulzo Y, Conrad M, Robert R, Gonzalez F, Guitton C, Tamion F, Tonnelier JM, Guezennec P, Van Der Linden T, Vieillard-Baron A, Mariotte E, Pradel G, Lesieur O, Ricard JD, Hervé F, du Cheyron D, Guerin C, Mercat A, Teboul JL, Radermacher P; SEPSISPAM Investigators. High versus low blood-pressure target in patients with septic shock. N Engl J Med. 2014 Apr 24;370(17):1583-93. doi: 10.1056/NEJMoa1312173. Epub 2014 Mar 18. PMID: 24635770.}

SOAP II trial: Dopamine vs Norepinephrine shock

Article Name: Comparison of Dopamine and Norepinephrine in the Treatment of Shock

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0907118

Journal and year of publication: NEJM, 2010

Trial Design: Randomized clinical trial

Population: 1,679 patients
Key inclusion criteria:
– Shock that needed a vasopressor agent
Key exclusion criteria:
– Patients declared brain-dead

Intervention Studied: Dopamine

Control: Norepinephrine

Outcomes:
– Rate of death (at 28 days): No significant difference between groups. Dopamine: 52.5% vs Norepinephrine: 48.5% (P=0.10)
– On subgroup analysis dopamine had increased rate of death in patients with cardiogenic shock
– Increased arrhythmic events with dopamine:24.1% vs Norepinephrine: 12.4%
(P<0.001)

The authors concluded that “Although there was no significant difference in the rate of death between patients with shock who were treated with dopamine as the first-line vasopressor agent and those who were treated with norepinephrine, the use of dopamine was associated with a greater number of adverse events.”

Citation: _{De Backer D, Biston P, Devriendt J, Madl C, Chochrad D, Aldecoa C, Brasseur A, Defrance P, Gottignies P, Vincent JL; SOAP II Investigators. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med. 2010 Mar 4;362(9):779-89. doi: 10.1056/NEJMoa0907118. PMID: 20200382.}

TRISS trial: Hemoglobin threshold for critical illness

Article Name: Lower versus Higher Hemoglobin Threshold for Transfusion in Septic Shock

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1406617

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 998 patients
Key inclusion criteria:
– Patients in ICU with septic shock and have a hemoglobin concentration of 9 g/dL or less
Key exclusion criteria:
– Brain death
– Acute burn injury

Intervention Studied: Transfuse with a hemoglobin level of 7 g/dL (lower threshold)

Control: Transfuse with a hemoglobin level of 9 g/dL (higher threshold)

Outcomes:
– Blood units received: Lower threshold group: Median of 1 unit (interquartile range, 0 to 3) vs Higher threshold group: Median of 4 units (interquartile range, 2 to 7).
– Deaths (at 90 days): Lower threshold group: 43.0% of patients vs Higher threshold group: 45.0% of patients (P=0.44)
– No difference between groups in regards to ischemic events, severe adverse reactions, and need of life support

The authors concluded that “Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions.”

Citation: _{Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S, Johansson PI, Aneman A, Vang ML, Winding R, Nebrich L, Nibro HL, Rasmussen BS, Lauridsen JR, Nielsen JS, Oldner A, Pettilä V, Cronhjort MB, Andersen LH, Pedersen UG, Reiter N, Wiis J, White JO, Russell L, Thornberg KJ, Hjortrup PB, Müller RG, Møller MH, Steensen M, Tjäder I, Kilsand K, Odeberg-Wernerman S, Sjøbø B, Bundgaard H, Thyø MA, Lodahl D, Mærkedahl R, Albeck C, Illum D, Kruse M, Winkel P, Perner A; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91. doi: 10.1056/NEJMoa1406617. Epub 2014 Oct 1. PMID: 25270275.}

SMART trial: IV fluid types for critically ill patients

Article Name: Balanced Crystalloids versus Saline in Critically Ill Adults

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1711584

Journal and year of publication: NEJM, 2018

Trial Design: Randomized clinical trial

Population: 15,802 patients
Key inclusion criteria:
– Patients admitted to the ICU
Key exclusion criteria:

Intervention Studied: Balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A)

Control: Saline (0.9% sodium chloride)

Outcomes:
– Major kidney events: Balanced-crystalloids group: 14.3% of patients vs Saline: 15.4% of patients (P=0.04)
– In-hospital mortality (at 30 days): Balanced-crystalloids group: 10.3% of patients vs Saline: 11.1% of patients (P=0.06)

The authors concluded that “Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline.”

Citation: _{Semler MW, Self WH, Wanderer JP, Ehrenfeld JM, Wang L, Byrne DW, Stollings JL, Kumar AB, Hughes CG, Hernandez A, Guillamondegui OD, May AK, Weavind L, Casey JD, Siew ED, Shaw AD, Bernard GR, Rice TW; SMART Investigators and the Pragmatic Critical Care Research Group. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27. PMID: 29485925; PMCID: PMC5846085.}

NICE SUGAR trial: Target glucose levels in critically ill patients

Article Name: Intensive versus Conventional Glucose Control in Critically Ill Patients

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0810625

Journal and year of publication: NEJM, 2009

Trial Design: Randomized clinical trial

Population: 6,104 patients
Key inclusion criteria:
– Patients admitted to ICU and expected to require treatment for 3 or more consecutive days
Key exclusion criteria:
– Admitted to ICU for treatment of DKA or hyperosmolar state

Intervention Studied: Intensive glucose control (Target: 81 to 108 mg/dL)

Control: Conventional glucose control (Target: 180 mg/dL or less)

Outcomes:
– Death: Intensive glucose control: 27.5% of patients vs Conventional glucose control: 24.9% of patients (P=0.02)
– Severe hypoglycemia (Glucose ≤40 mg/dL): Intensive glucose control: 6.8% of patients vs Conventional glucose control: 0.5% (P<0.001)

The authors concluded that ” In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter.”

Citation: _{NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi: 10.1056/NEJMoa0810625. Epub 2009 Mar 24. PMID: 19318384.}

Daily sedation interruption for mechanically ventilated patients

Article Name: Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation

URL: https://www.nejm.org/doi/full/10.1056/NEJM200005183422002

Journal and year of publication: NEJM, 2000

Trial Design: Randomized clinical trial

Population: 128 patients
Key inclusion criteria:
– ICU patients, intubated and on mechanical ventilation
– Require sedation by continuous intravenous infusion
Key exclusion criteria:
– Admission after resuscitation from cardiac arrest

Intervention Studied: Interruption of sedative infusions, on a daily basis, until the patients were awake

Control: Continuous infusions, interrupted only at the discretion of the clinicians in ICU

Outcomes:
– Median duration of Mechanical ventilation: Intervention group: 4.9 days vs Control group: 7.3 days (P=0.004)
– Median length of stay in ICU: Intervention group: 6.4 days vs Control group: 9.9 days (P=0.02)
– Undergoing diagnostic testing due to changes in mental status: Intervention group: 9% of patients vs Control group: 27% of patients (P=0.02)

The authors concluded that ” In patients who are receiving mechanical ventilation, daily interruption of sedative-drug infusions decreases the duration of mechanical ventilation and the length of stay in the intensive care unit.“

Citation: _{Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000 May 18;342(20):1471-7. doi: 10.1056/NEJM200005183422002. PMID: 10816184.}

ARDSNet trial: Low tidal volume for ARDS

Article Name: Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome

URL: https://www.nejm.org/doi/full/10.1056/NEJM200005043421801

Journal and year of publication: NEJM, 2000

Trial Design: Randomized clinical trial

Population: 861 patients
Key inclusion criteria:
– Intubated and mechanically ventilated
– Acute decrease in the ratio of P_aO₂ to FiO₂ to 300 or less
– Bilateral pulmonary infiltrates on a chest radiograph consistent with the presence of edema
Key exclusion criteria:
– Neuromuscular disease which might impair spontaneous breathing
– Sickle cell disease, or severe chronic respiratory disease

Intervention Studied: Ventilation with a lower tidal volume (6 ml per kilogram, and plateau pressure of 30 cm of water or less)

Control: Traditional ventilation treatment (initial tidal volume of 12 ml per kilogram and plateau pressure of 50 cm of water or less)

Outcomes:
– Mortality: Lower tidal volume: 31.0% vs Traditional tidal volume: 39.8% (P=0.007)
– Number of days without a need for ventilator ( out of the first 28 days):
Lower tidal volume: 12 days vs Traditional tidal volume: 10 days (P=0.007)

The authors concluded that ” In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.“

Citation: _{Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1301-8. doi: 10.1056/NEJM200005043421801. PMID: 10793162.}

PROSEVA trial: Proning for ARDS

Article Name: Prone Positioning in Severe Acute Respiratory Distress Syndrome

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1214103

Journal and year of publication: NEJM, 2013

Trial Design: Randomized clinical trial

Population: 861 patients
Key inclusion criteria:
– Severe ARDS
– Endotracheal intubation and mechanical ventilation for ARDS for <36 hours
Key exclusion criteria:
– Contraindication for prone positioning
– Use of ECMO before inclusion
– Lung transplantation
– Burns >20%

Intervention Studied: Prone-positioning sessions of at least 16 hours

Control: Left in supine position

Outcomes:
– 28-day Mortality: Prone group: 16.0% vs Supine group: 32.8% (P<0.001)
– Unadjusted 90-day mortality: Prone group: 23.6% vs Supine group: 41.0% (P<0.001)

The authors concluded that “In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality.”

Citation: _{Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, Mercier E, Badet M, Mercat A, Baudin O, Clavel M, Chatellier D, Jaber S, Rosselli S, Mancebo J, Sirodot M, Hilbert G, Bengler C, Richecoeur J, Gainnier M, Bayle F, Bourdin G, Leray V, Girard R, Baboi L, Ayzac L; PROSEVA Study Group. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159-68. doi: 10.1056/NEJMoa1214103. Epub 2013 May 20. PMID: 23688302.}

ROSE trial: Neuromuscular blockade for ARDS

Article Name: Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1901686

Journal and year of publication: NEJM, 2019

Trial Design: Randomized clinical trial

Population: 1,006 patients
Key inclusion criteria:
– Endotracheal intubation and mechanical ventilation
– Pao₂:Fio₂ <150 mm Hg with a PEEP of 8 cm or more of water
– Bilateral pulmonary opacities on CXR or CT that could not be explained by effusions, pulmonary collapse, or nodules
– Respiratory failure not due to cardiac failure or fluid overload
Key exclusion criteria:
– On ECMO
– Chronic respiratory failure, PaCO2 >60 mmHg in the outpatient setting
– Body weight exceeding 1 kg per centimeter of height

Intervention Studied: 48-hour continuous infusion of cisatracurium with concomitant deep sedation

Control: Usual-care approach without routine neuromuscular blockade and with lighter sedation targets

Outcomes:
– Death before discharge (At 90 days): Intervention group: 42.5% vs Control group: 42.8% (P=0.93)
– During their hospital stay, patient in the intervention group were less physically active and had more adverse cardiovascular events

The authors concluded that “Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets.”

Citation: _{National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, Brower RG, Ferguson ND, Ginde AA, Gong MN, Grissom CK, Gundel S, Hayden D, Hite RD, Hou PC, Hough CL, Iwashyna TJ, Khan A, Liu KD, Talmor D, Thompson BT, Ulysse CA, Yealy DM, Angus DC. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019 May 23;380(21):1997-2008. doi: 10.1056/NEJMoa1901686. Epub 2019 May 19. PMID: 31112383; PMCID: PMC6741345.}

3SITES trial: Location of central venous catheter placement

Article Name: Intravascular Complications of Central Venous Catheterization by Insertion Site

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1500964

Journal and year of publication: NEJM, 2015

Trial Design: Randomized clinical trial

Population: 3471 catheters in 3027 patients
Key inclusion criteria:
– Admitted to the ICU
– Needed nontunneled central venous vascular access
– Suitable candidates for catheterization in at least 2 out of the 3 sites: Subclavian veins, Jugular veins, Femoral veins
Key exclusion criteria:

Intervention Studied: Central venous catheter insertion through:
1) Subclavian vein
2) Jugular vein
3) Femoral vein

Control: See above

Outcomes:
– Primary outcome events(composite of CRBSI and symptomatic DVT):
Subclavian vein: 8 events (1.5 per 1000 catheter-days)
Jugular vein: 20 events (3.6 per 1000 catheter-days)
Femoral vein: 22 events (4.6 per 1000 catheter-days)
(P=0.02)
– Pneumothorax requiring chest-tube insertion occurrence: Subclavian group: 1.5% of patients vs Jugular group: 0.5% of patients

The authors concluded that “In this trial, subclavian-vein catheterization was associated with a lower risk of bloodstream infection and symptomatic thrombosis and a higher risk of pneumothorax than jugular-vein or femoral-vein catheterization.”

Citation: _{Parienti JJ, Mongardon N, Mégarbane B, Mira JP, Kalfon P, Gros A, Marqué S, Thuong M, Pottier V, Ramakers M, Savary B, Seguin A, Valette X, Terzi N, Sauneuf B, Cattoir V, Mermel LA, du Cheyron D; 3SITES Study Group. Intravascular Complications of Central Venous Catheterization by Insertion Site. N Engl J Med. 2015 Sep 24;373(13):1220-9. doi: 10.1056/NEJMoa1500964. PMID: 26398070.}

Reducing CLABSI trial

Article Name: An Intervention to Decrease Catheter-Related Bloodstream Infections in the ICU

URL: https://www.nejm.org/doi/full/10.1056/nejmoa061115

Journal and year of publication: NEJM, 2006

Trial Design: Prospective cohort study

Population: 108 ICUs, 375,757 catheter-days

Key inclusion criteria:
– All Michigan hospitals with ICUs for adults were invited

Intervention Studied:
Each ICU implemented several patient-safety interventions. The study intervention targeted clinicians’ use of five evidence-based procedures recommended by the CDC and identified as having the greatest effect on the rate of catheter-related bloodstream infection: hand washing, using full-barrier precautions during the insertion of central venous catheters, cleaning the skin with chlorhexidine, avoiding the femoral site if possible, and removing unnecessary catheters.

Clinicians were educated about practices to control infection and harm resulting from catheter-related bloodstream infections, a central-line cart with necessary supplies was created, a checklist was used to ensure adherence to infection-control practices, providers were stopped (in nonemergency situations) if these practices were not being followed, the removal of catheters was discussed at daily rounds, and the teams received feedback regarding the number and rates of catheter-related bloodstream infection at monthly and quarterly meetings, respectively.

Control: N/A

Outcomes:
– The median rate of catheter-related bloodstream infection per 1000 catheter-days decreased from 2.7 infections at baseline to 0 at 3 months after implementation of the study intervention (P≤0.002), and the mean rate per 1000 catheter-days decreased from 7.7 at baseline to 1.4 at 16 to 18 months of follow-up (P<0.002).

The authors concluded that “An evidence-based intervention resulted in a large and sustained reduction (up to 66%) in rates of catheter-related bloodstream infection that was maintained throughout the 18-month study period.”

Citation: _{Pronovost P, Needham D, Berenholtz S, Sinopoli D, Chu H, Cosgrove S, Sexton B, Hyzy R, Welsh R, Roth G, Bander J, Kepros J, Goeschel C. An intervention to decrease catheter-related bloodstream infections in the ICU. N Engl J Med. 2006 Dec 28;355(26):2725-32. doi: 10.1056/NEJMoa061115. Erratum in: N Engl J Med. 2007 Jun 21;356(25):2660. PMID: 17192537.}

Pulmonology

Novel START trial: Budesonide-Formoterol PRN for asthma

Article Name: Controlled Trial of Budesonide–Formoterol as Needed for Mild Asthma

URL: https://www.nejm.org/doi/10.1056/NEJMoa1901963

Journal and year of publication: NEJM, 2019

Trial Design: Randomized clinical trial

Population: 675 patients
Key inclusion criteria:
– 18 to 75 years of age diagnosed with Asthma
– Using SABA as the sole asthma therapy in the previous 3 months
Key exclusion criteria:
– Hospitalization for asthma in the past 12 months

Intervention Studied:
1) Albuterol PRN (Albuterol group)
2) Budesonide + Albuterol PRN (Budesonide maintenance group)
3) Budesonide–formoterol PRN (Budesonide–formoterol group)

Control: See above

Outcomes:
– Annualized exacerbation rate: Budesonide–formoterol group: 0.195 vs Albuterol group: 0.400 vs Budesonide maintenance group: 0.175
– Relative risks:
Budesonide–formoterol group was lower than Albuterol group (P<0.001)
No significant difference between Budesonide–formoterol group and Budesonide maintenance group (P=0.65)

The authors concluded that “In an open-label trial involving adults with mild asthma, budesonide–formoterol used as needed was superior to albuterol used as needed for the prevention of asthma exacerbations.”

Citation: _{Beasley R, Holliday M, Reddel HK, Braithwaite I, Ebmeier S, Hancox RJ, Harrison T, Houghton C, Oldfield K, Papi A, Pavord ID, Williams M, Weatherall M; Novel START Study Team. Controlled Trial of Budesonide-Formoterol as Needed for Mild Asthma. N Engl J Med. 2019 May 23;380(21):2020-2030. doi: 10.1056/NEJMoa1901963. Epub 2019 May 19. PMID: 31112386.}

SYGMA 2 trial: Budesonide-Formoterol PRN vs budesonide for asthma

Article Name: As-Needed Budesonide–Formoterol versus Maintenance Budesonide in Mild Asthma

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1715275

Journal and year of publication: NEJM, 2018

Trial Design: Randomized clinical trial

Population: 4,215 patients
Key inclusion criteria:
– Outpatients aged 12 years or above
– Diagnosis of asthma according to GINA 6 months before visit 1 and in need of GINA (2012) Step 2 treatments
Key exclusion criteria:
– Asthma worsening requiring treatment other than inhaled SABA and/or SAMA within 30 days prior to Visit 1
– Use of any β-blocking agent including eye-drops
– Smoking history of ≥10 pack-years (current or previous)

Intervention Studied:
Twice-daily placebo + budesonide–formoterol (200 μg of budesonide and 6 μg of formoterol) used as needed

Control:
Budesonide maintenance therapy with twice-daily budesonide (200 μg) plus terbutaline (0.5 mg) used as needed

Outcomes:
– Annualised rate of severe exacerbations: Budesonide–formoterol: 0.11 (95% CI: 0.10 – 0.13) vs Budesonide maintenance therapy: 0.12 (95% CI: 0.10 – 0.14)
– Median daily metered dose of inhaled glucocorticoids: Lower in budesonide–formoterol group (66 μg) vs budesonide maintenance group (267 μg)
– Change in ACQ-5 score: Favouring budesonide maintenance therapy:
Difference of 0.11 units (95% CI: 0.07 – 0.15)

The authors concluded that “In patients with mild asthma, budesonide–formoterol used as needed was noninferior to twice-daily budesonide with respect to the rate of severe asthma exacerbations during 52 weeks of treatment but was inferior in controlling symptoms. Patients in the budesonide–formoterol group had approximately one quarter of the inhaled glucocorticoid exposure of those in the budesonide maintenance group.”

Citation: _{Bateman, E. D., Reddel, H. K., O’Byrne, P. M., Barnes, P. J., Zhong, N., Keen, C., Jorup, C., Lamarca, R., Siwek-Posluszna, A., & FitzGerald, J. M. (2018). As-Needed Budesonide-Formoterol versus Maintenance Budesonide in Mild Asthma. The New England journal of medicine, 378(20), 1877–1887. https://doi.org/10.1056/NEJMoa1715275}

Similar study:
SYGMA 1 trial: Inhaled Combined Budesonide–Formoterol as Needed in Mild Asthma. URL: https://www.nejm.org/doi/full/10.1056/nejmoa1715274

EXTRA trial: Omalizumab for severe asthma

Article Name: Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy

URL: https://www.acpjournals.org/doi/full/10.7326/0003-4819-154-9-201105030-00002

Journal and year of publication: Annals of Internal Medicine, 2011

Trial Design: Randomized clinical trial

Population: 850 patients
Key inclusion criteria:
– 12 to 75 years with severe allergic asthma
– Asthma was not well-controlled despite treatment with high-dose ICS and LABAs
Key exclusion criteria:
– Active lung disease other than asthma
– Elevated serum IgE levels for reasons other than allergy

Intervention Studied: Omalizumab

Control: Placebo

Outcomes:
– Rate of asthma exacerbations (by 48 weeks): Omalizumab: 0.66 per patient vs Placebo: 0.88 per patient (P = 0.006)
– Adverse events: No significant difference in the incidence of adverse events or severe adverse events between the 2 groups

The authors concluded that “In this study, omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy.”

Citation: _{Hanania NA, Alpan O, Hamilos DL, Condemi JJ, Reyes-Rivera I, Zhu J, Rosen KE, Eisner MD, Wong DA, Busse W. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011 May 3;154(9):573-82. doi: 10.7326/0003-4819-154-9-201105030-00002. Erratum in: Ann Intern Med. 2019 Oct 1;171(7):528. PMID: 21536936.}

TORCH trial: Salmeterol and Fluticasone for COPD

Article Name: Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa063070#t=abstract

Journal and year of publication: NEJM, 2007

Trial Design: Randomized clinical trial

Population: 6,112 patients
Key inclusion criteria:
– Current or former smokers with at least a 10-pack-year history.
– 40 to 80 years of age diagnosed with COPD
Key exclusion criteria:
– Lung-volume reduction surgery and/or lung transplantation
– A requirement for long-term (≥12 h per day) oxygen therapy
– Known α-1 antitrypsin deficiency

Intervention Studied:
1) Salmeterol + fluticasone propionate twice daily (Combination regimen)
2) Salmeterol alone
3) Fluticasone propionate alone

Control: Placebo

Outcomes:
– All-cause mortality rates: Combination regimen: 12.6% vs Placebo: 15.2% vs Salmeterol alone: 13.5% vs Fluticasone propionate alone: 16.0% (P=0.052)
– Annual rate of exacerbations: Combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85, when compared with placebo (P<0.001)
– Probability of having pneumonia: Combination regimen: 19.6%, Fluticasone propionate alone: 18.3%, Placebo: 12.3% (P<0.001)

The authors concluded that “The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance. There were significant benefits in all other outcomes among these patients.”

Citation: _{Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007 Feb 22;356(8):775-89. doi: 10.1056/NEJMoa063070. PMID: 17314337.}

UPLIFT trial: Tiotropium for COPD

Article Name: A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0805800

Journal and year of publication: NEJM, 2008

Trial Design: Randomized clinical trial

Population: 5,993 patients
Key inclusion criteria:
– Aged 40 years or more, with a diagnosis of COPD
– Smoking history of at least 10 pack-years
Key exclusion criteria:
– History of asthma
– Pulmonary resection
– Supplemental oxygen >12 hours/day

Intervention Studied: Tiotropium

Control: Placebo

Outcomes:
– Mean absolute improvements in FEV1 with tiotropium, when compared to placebo (P<0.001):
Before bronchodilation: 87 to 103 ml
After bronchodilation: 47 to 65 ml
– Mean absolute total SGRQ score: Improved (lower) with tiotropium vs placebo, ranging from 2.3 to 3.3 units (P<0.001)
– At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure

The authors concluded that “In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV₁.”

Citation: _{Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008 Oct 9;359(15):1543-54. doi: 10.1056/NEJMoa0805800. Epub 2008 Oct 5. PMID: 18836213.}

POET-COPD trial: Tiotropium vs Salmeterol for COPD

Article Name: Tiotropium versus Salmeterol for the Prevention of Exacerbations of COPD

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1008378

Journal and year of publication: NEJM, 2011

Trial Design: Randomized clinical trial

Population: 7,376 patients
Key inclusion criteria:
– ≥ 40 years of age with a ≥10 pack-years smoking history
– Diagnosis of COPD:
– At least one exacerbation in the past year
Key exclusion criteria:
– Asthma diagnosis or cystic fibrosis
– History in the past year of MI or hospital admission for HF

Intervention Studied: 18 μg of tiotropium once daily

Control: 50 μg of salmeterol twice daily

Outcomes:
– Time to first exacerbation long with Tiotropium, vs salmeterol:
Tiotropium: 187 days vs Salmeterol: 145 days; 17% reduction in risk: HR: 0.83 (95% CI: 0.77 – 0.90), P<0.001
– Annual number of moderate or severe exacerbations: Tiotropium: 0.64 vs Salmeterol: 0.72, Rate ratio: 0.89 95% CI: 0.83 – 0.96 (P=0.002)

The authors concluded that “These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations.“

Citation: _{Vogelmeier, C., Hederer, B., Glaab, T., Schmidt, H., Rutten-van Mölken, M. P., Beeh, K. M., Rabe, K. F., Fabbri, L. M., & POET-COPD Investigators (2011). Tiotropium versus salmeterol for the prevention of exacerbations of COPD. The New England journal of medicine, 364(12), 1093–1103. https://doi.org/10.1056/NEJMoa1008378}

REDUCE trial: Duration of steroids for acute COPD exacerbation

Article Name: Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease

URL: https://jamanetwork.com/journals/jama/fullarticle/1688035

Journal and year of publication: JAMA, 2013

Trial Design: Randomized clinical trial

Population: 314 patients
Key inclusion criteria:
– >40 years old with an exacerbation of COPD
– Smoking history of 20 pack-years or more
Key exclusion criteria:
– History of asthma
– Radiological diagnosis of pneumonia

Intervention Studied: Prednisone daily for 5 days (short term therapy)

Control: Prednisone daily for 14 days (conventional therapy)

Outcomes:
– Primary endpoint (time to next COPD exacerbation during 6 months): Short term: 35.9% vs Conventional therapy: 36.8%
– No significant difference between groups in regards to: Time to death; Combined end point of exacerbation, death, or both; Recovery of lung function

The authors concluded that “In patients presenting to the emergency department with acute exacerbations of COPD, 5-day treatment with systemic glucocorticoids was noninferior to 14-day treatment with regard to reexacerbation within 6 months of follow-up but significantly reduced glucocorticoid exposure. These findings support the use of a 5-day glucocorticoid treatment in acute exacerbations of COPD.”

Citation: _{Leuppi JD, Schuetz P, Bingisser R, Bodmer M, Briel M, Drescher T, Duerring U, Henzen C, Leibbrandt Y, Maier S, Miedinger D, Müller B, Scherr A, Schindler C, Stoeckli R, Viatte S, von Garnier C, Tamm M, Rutishauser J. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013 Jun 5;309(21):2223-31. doi: 10.1001/jama.2013.5023. PMID: 23695200.}

NETT trial: Lung volume reduction for severe COPD

Article Name: A Randomized Trial Comparing Lung-Volume–Reduction Surgery with Medical Therapy for Severe Emphysema

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa030287

Journal and year of publication: NEJM, 2003

Trial Design: Randomized clinical trial

Population: 1,218 patients
Key inclusion criteria:
– Severe emphysema
– Non Smoker for the past 4 months and throughout screening
Key exclusion criteria:
– Pulmonary hypertension
– Giant bulla (≥1⁄3 of the volume of the lung)
– Clinically significant bronchiectasis

Intervention Studied: Lung-volume–reduction surgery

Control: Continued medical treatment

Outcomes:
– Mortality outcomes: Surgery: 0.09 death per person-year vs Medical therapy: 0.10 death per person-year (P=0.31)
– Subgroup analysis:
– Patients with predominantly upper-lobe emphysema and low exercise capacity:
Lower mortality with surgery, vs medical therapy: Risk ratio for death: 0.47 (P=0.005)
– Patients with non–upper-lobe emphysema and high exercise capacity:
Higher mortality with the surgery, vs medical therapy Risk ratio: 2.06 (P=0.02)
– Exercise capacity: Surgery group: Improved in 15% of patients vs Medical therapy: 3% of patients (P<0.001)

The authors concluded that ” Overall, lung-volume–reduction surgery increases the chance of improved exercise capacity but does not confer a survival advantage over medical therapy. It does yield a survival advantage for patients with both predominantly upper-lobe emphysema and low base-line exercise capacity. Patients previously reported to be at high risk and those with non–upper-lobe emphysema and high base-line exercise capacity are poor candidates for lung-volume–reduction surgery, because of increased mortality and negligible functional gain.”

Citation: _{Fishman A, Martinez F, Naunheim K, Piantadosi S, Wise R, Ries A, Weinmann G, Wood DE; National Emphysema Treatment Trial Research Group. A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. N Engl J Med. 2003 May 22;348(21):2059-73. doi: 10.1056/NEJMoa030287. Epub 2003 May 20. PMID: 12759479.}

ASCEND trial: Pirfenidone for IPF

Article Name: A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1402582

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 555 patients
Key inclusion criteria:
– Diagnosis of idiopathic pulmonary fibrosis.
– Range of 50 to 90% of the predicted FVC.
– Range of 30 to 90% of the predicted carbon monoxide diffusing capacity
Key exclusion criteria:
– Known explanation for interstitial lung disease
– Diagnosis of any connective tissue disease
– History of asthma or COPD

Intervention Studied: Oral pirfenidone

Control: Placebo

Outcomes:
– When compared to placebo, in the pirfenidone group, there was:
– A 47.9% relative reduction in proportion of patients with an absolute decline of 10% points or more in the percentage of the predicted FVC or who died and a 132.5% relative increase in proportion of patients with no decline in FVC (P<0.001)
– Reduction of the decline in the 6-minute walk distance (P=0.04)
– Improvement in progression-free survival (P<0.001)

The authors concluded that ” Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival, in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side-effect profile and fewer deaths.”

Citation: _{King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, Sahn SA, Sussman R, Swigris JJ, Noble PW; ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2083-92. doi: 10.1056/NEJMoa1402582. Epub 2014 May 18. Erratum in: N Engl J Med. 2014 Sep 18;371(12):1172. PMID: 24836312.}

INPULSIS trial: Nintedanib for IPF

Article Name: Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1402584

Journal and year of publication: NEJM, 2014

Trial Design: Randomized clinical trial

Population: 1,066 patients (INPULSIS-1 and INPULSIS-2)
Key inclusion criteria:
– Diagnosed with IPF within the past 5 years
– FVC 50% or more of the predicted value
– DLCO 30 to 79% of the predicted value
Key exclusion criteria:
– On therapy for IPF(i.e high-dose prednisone, azathioprine, N-acetylcysteine)

Intervention Studied: Nintedanib

Control: Placebo

Outcomes:
– Adjusted annual rate of change in FVC:
– INPULSIS-1: Nintedanib: −114.7 ml vs Placebo: −239.9 ml (P<0.001)
– INPULSIS-2: Nintedanib: −113.6 ml vs Placebo: −207.3 ml (P<0.001)
– The most common adverse event with nintedanib was diarrhea

The authors concluded that “In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients.”

Citation: _{Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014 May 29;370(22):2071-82. doi: 10.1056/NEJMoa1402584. Epub 2014 May 18. Erratum in: N Engl J Med. 2015 Aug 20;373(8):782. PMID: 24836310}

ARIES trial: Ambrisentan for PAH

Article Name: Long-Term Ambrisentan Therapy for the Treatment of Pulmonary Arterial Hypertension

URL: https://www.sciencedirect.com/science/article/pii/S0735109709028423?via%3Dihub

Journal and year of publication: Journal of the American College of Cardiology, 2009

Trial Design: Randomized clinical trial

Population: 202 patients + 192 patients
Key inclusion criteria:
– Idiopathic PAH, PAH associated with CTD, human immunodeficiency virus infection, or anorexigen use
– Acceptable LFTs level
Key exclusion criteria:

Intervention Studied: Ambrisentan in varying doses (2.5mg to 10 mg)

Control: Placebo

Outcomes:
– Mean change from baseline 6-min walk distance (after 2 years): Ambrisentan 5 mg: +23 m (95% CI: 9 to 38 m) vs Ambrisentan 10 mg:+28 m(95% CI: 11 to 45 m)
– Estimated survival rates in all treatment groups combined: At 1 year: 94%; At 2 years: 88%

The authors concluded that “Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period.”

Citation: _{Oudiz RJ, Galiè N, Olschewski H, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Harrison BC, Despain D, Dufton C, Rubin LJ; ARIES Study Group. Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension. J Am Coll Cardiol. 2009 Nov 17;54(21):1971-81. doi: 10.1016/j.jacc.2009.07.033. PMID: 19909879.}

SUPER-1 trial: Sildenafil for PAH

Article Name: Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension

URL: https://www.nejm.org/doi/full/10.1056/nejmoa050010

Journal and year of publication: NEJM, 2005

Trial Design: Randomized clinical trial

Population: 278 patients
Key inclusion criteria:
– PAH (idiopathic, associated CTD, or after surgical repair of congenital systemic-to-pulmonary shunts performed at least five years previously)
Key exclusion criteria:
– 6-minute walking distance <100 m OR >450 m

Intervention Studied: Sildenafil

Control: Placebo

Outcomes:
– Increment in the 6 minutes walking distance from baseline with sildenafil:
Sildenafil 20 mg: 45 m (+13%); Sildenafil 40 mg: 46 m (+13.3%); Sildenafil 80 mg: 50 m (+14.7%) (P<0.001 for all comparisons)
– Mean pulmonary-artery pressure was reduced with all doses of Sildenafil.
Sildenafil 20 mg: P=0.04; 40 mg:P=0.01; 80 mg: P<0.001
– WHO functional class was improved with all doses of sildenafil: Sildenafil 20 mg:P=0.003; 40 mg: P<0.001; 80 mg: P<0.001

The authors concluded that “Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.”

Citation: _{Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med. 2005 Nov 17;353(20):2148-57. doi: 10.1056/NEJMoa050010. Erratum in: N Engl J Med. 2006 Jun 1;354(22):2400-1. PMID: 16291984.}

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