Oxygen therapy for pneumonia in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effect and safety of oxygen therapy in the treatment of pneumonia.
Background
Description of the condition
Pneumonia is defined as an acute lower respiratory tract infection accompanied by new radiographic shadowing on chest X‐ray (BTS 2001). Common clinical symptoms of pneumonia may include cough, sputum production, fever, chills, fatigue, shortness of breath, night sweats and pleuritic chest pain. It is most common in young children and elderly people. However it can affect anyone. It can be caused by bacteria, viruses, mycoplasma, chlamydia, fungi or parasites; almost 100 species have been identified as pathogens (Donowitz 2000; Fine 2003). It may be called community‐acquired pneumonia (CAP) or nosocomial (hospital‐acquired) pneumonia (NP or HAP). The clinical presentations are often similar in both. Streptococcus pneumoniae (S. pneumoniae) is responsible for CAP in 40% of patients. HAP is often caused by gram negative organisms. The annual incidence of CAP is 6/1000 in those aged 18 to 59 years old, 20/1000 for those aged 60 years and over, and rises to 34/1000 in people aged 75 years and over (Jokinen 1993). Admission to hospital is needed in 20 to 40% of patients with CAP (BTS 2001; Macfarlane 2004).
Both CAP and HAP are associated with a significant mortality (Fagon 1993). HAP is the leading cause of mortality in hospital‐acquired infections (Flanders 2006). In low‐income countries, pneumonia causes approximately two million deaths annually among children under five years of age (Graham 1990; Jones 2003; Rudan 2004). In the USA, pneumonia is the sixth most common cause of death and the most common cause of infection‐related mortality (Donowitz 2000).
Description of the intervention
Prescribed oxygen may be described in both volume (dosage) and delivery system terms. Low volume systems include nasal cannulae (NC), shields and masks. Drawbacks to low volume systems include drying of the nasal mucosa and eyes; discomfort, as masks can pinch and cause skin irritation; and their passive delivery system is dependent on the patient's ability to breathe. If the lungs cannot keep the body oxygenated using these methods, mechanical ventilation may be required. The most common respiratory support is non‐invasive positive pressure ventilation (NIPPV), continuous positive airway pressure (CPAP) and invasive positive pressure ventilation (IPPV). The disadvantages of mechanical ventilation are twofold: chest muscles can weaken through disuse and bacteria may better access the lungs.
Oxygen therapy is often only necessary in severe cases of pneumonia ('severe' defined as a "confusion, urea > 7 mmol/l, respiratory rate >= 30/min, low systolic (< 90 mm Hg) or diastolic (<= 60 mm Hg) blood pressure, age >= 65 years score", (or "CURB‐65 score") of 3 or more) (Ewig 2006; Lim 2003) or in those patients with hypoxemia (partial pressure of oxygen in artery (PaO2) less than 8 Kpa) or oxygen saturation (SaO2) less than 92% (ATS 2001). It has been suggested that oxygen saturation should be maintained at a level above 90% in patients with pneumonia (Alvin 2004). Mortality from pneumonia has been shown to be related to arterial blood oxygen saturation (Onyango 1993), the presence of bacteremia, the serotype of the organism (in pneumococcal pneumonia) and the age of the patient (Cecil 1927).
Oxygen was first isolated by Priestley in 1744 and used therapeutically by Beddoes in 1798 (Boothby 1932). In 1885 George E. Holtzapple, MD, discovered that oxygen could be used to treat pneumonia. Stadie reported that the mortality in patients with pneumonia was 39% with oxygen and 74% without oxygen, after data were adjusted for the severity of the illness (Stadie 1919; Stadie 1922). Clinical pathway treatment includes oxygen saturation monitoring and oxygen delivery, which can reduce hospitalization significantly (Loeb 2006). There is consensus among scientists and clinicians of the life‐saving benefits of oxygen therapy for patients with severe pneumonia and signs of decreased oxygen saturation. The World Health Organization (WHO) recommends oxygen therapy for children with pneumonia (WHO 1990). Inconsistent results on the effect of oxygen therapy for pneumonia were reported in some trials. Several studies have reported that provision of NIPPV in patients with severe CAP can lead to initial improvement (Antonelli 2001; Domenighetti 2002; Jolliet 2001). NIPPV, as either CPAP or bi‐level pressure support, can improve patients' oxygenation and tachypnea in severe acute respiratory syndrome cases (Chen 2003; Cheung 2004; Li 2003). A study from Hong Kong also draws the same conclusion (Yam 2005). In contrast, a study indicated NIPPV for CAP should only be administered in an appropriate critical care setting, because over half of these patients later deteriorated and required intubation (Kinnear 2002). Despite early physiologic improvements, CPAP neither reduced the need for intubation nor improved outcomes in patients with acute hypoxemic, nonhypercapnic respiratory insufficiency primarily due to acute lung injury, including pneumonia (Delclaux 2000).
Why it is important to do this review
Oxygen therapy for individuals with hypoxemia is commonly prescribed. However, no systematic review has previously been conducted on patients with non‐hypoxemic pneumonia and looking at which oxygen therapy is the best for them.
Objectives
To assess the effect and safety of oxygen therapy in the treatment of pneumonia.
Methods
Criteria for considering studies for this review
Types of studies
Only randomized controlled trial (RCT) and quasi‐RCT will be included.
Types of participants
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Patients with both CAP and HAP will be included in this review.
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Patients aged 18 years and over, diagnosed with pneumonia, with or without lung cancer, immune deficiency, drug or systemic disease induced immunosuppression; and mechanically ventilated patients will all be included.
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Trials on patients with pulmonary tuberculosis and cystic fibrosis will be excluded because of their very different prognoses. If the indication for treatment consists of multiple diagnoses (most commonly: acute bronchitis, exacerbation of chronic bronchitis, and pneumonia) and the results are reported separately for each diagnostic group, these trials will be considered for inclusion.
Types of interventions
Any oxygen therapy, regardless of dosage and delivery system. Oxygen therapy, either administered alone or as an adjunctive therapy (co‐interventions include antibiotic, mucolytic agents, fluid supplements, etc) will be compared with a placebo or one form of oxygen therapy with another form (for example, at different dosages or by delivery systems).
Types of outcome measures
Primary outcomes
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Mortality from respiratory causes.
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Clinical response: improvement in signs and symptoms, and duration of clinical signs and symptoms. A clinical definition of cure will be used as the primary outcome since radiographic resolution lags behind clinical improvement.
Secondary outcomes
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All causes mortality.
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Dyspnea score.
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Arterial blood gas (ABG) measurements.
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Duration of hospitalization.
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Requirement of ICU for patients treated initially outside the ICU.
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Mental status score: tests to assess mental status will be considered as acceptable. For example: abbreviated mental test (AMT) score 192.
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The incidence rate for ventilating patients who either have O2 alone or no O2; and the incidence rate for invasive ventilation in patients who have been treated with CPAP or NIPPV.
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Rate of complications of pneumonia (for example, parapneumonic effusions and empyema, lung abscess, septic shock, multiple organ failure).
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Any adverse events, including: drying of the nasal mucosa and eyes; discomfort (as masks can pinch and cause skin irritation); chest muscles weakness; bacterial lung infection.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue), which includes the Cochrane Acute Respiratory Infections Group's specialized trials register; MEDLINE (1966 to present); EMBASE (1974 to present); and LILACS (1982 to present).
CENTRAL and MEDLINE will be searched using the following terms and they will be adapted for EMBASE and LILACS as necessary.
MEDLINE (Ovid)
#1 exp Pneumonia
#2 *pneumon*
#3 exp Community‐acquired pneumonia
#4 exp Hospital‐acquired pneumonia
#5 CAP
#6 exp HAP
#7 exp Bronchopneumonia
#8 exp Pleuropneumonia
#9 exp Community‐Acquired Infections
#10 exp respiratory tract infection
#11 exp nosocomial pneumonia
#12 exp ventilator associated pneumonia
#13 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR#12
#14 oxygen* AND therap*
#15 oxygen* AND inhal*
#16 O2* AND therap*
#17 O2* AND (inhal* or respiratory*)
#18 nasal cannula*
#19 nasal prong*
#20 NRM
#21 venture*
#22 Hudson*
#23 mask*
#24 non invasive positive pressure ventilation
#25 non invasive ventilation
#26 exp Mechanical ventilation
#27 #14 OR #15#16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26
#28 Randomized‐Controlled‐Trial
#29 controlled‐clinical‐trial
#30 exp Randomized‐Controlled‐Trials
#31 exp Random‐Allocation
#32 exp Single‐Blind‐Method
#33 exp Double‐Blind‐Method
#34 comparative study/
#35 exp evaluation studies/
#36 follow‐up studies/
#37 prospective studies/
#38 (control$ or prospectiv$ or volunteer$).tw.
#39 #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38
#40 TG=human
#41 (TG=animal) not ((TG=animal) and (TG=human))
#42 #40 not #41
#43 adults
#44 children or infants
#45 #43 not #44
#46 #13 AND #39 AND #42 AND #45
We will search for on going trials in following registers: ClinicalTrial.gov (http://clintrial.gov/); Chinese Clinical Trial Register (www.chictr.org); Australian Clinical Trials Registry http://www.actgr.org.au/); ISRCTN (http://www.controlled‐trials.com/isrctn/); and WHO ICTRP.
Searching other resources
The references of all included trials will be scanned to identify other relevant trials. In addition, we plan to identify any other reviews or meta‐analyses on this topic. Appropriate journals will be handsearched. To identify any additional unpublished studies, we will contact ventilator‐manufacturing companies or authors of relevant unpublished articles. There will be no language or publication restrictions.
Data collection and analysis
Selection of studies
Two review authors (YZ, ZX) will independently select relevant articles and assess their eligibility according to the inclusion and exclusion criteria, resolving any disagreements by discussion. Two other review authors (BD, TW) will be consulted if necessary. We will obtain the full text for those articles identified as either relevant or ambiguous from their titles and abstracts.
Quality assessment
We will assess the methodological quality of each trial in terms of generation of allocation sequence, allocation concealment, blinding, and loss to follow up; and classify them as 'adequate', 'inadequate', or 'unclear' according to the guidelines of Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2005) and described by Wu 2007. Sensitivity analyses will then be undertaken on the basis of whether those quality factors are adequate, inadequate, or unclear. Differences will be resolved by discussion among the review authors.
The following characteristics will be assessed:
Adequacy of the randomization process
A ‐ adequate sequence generation is reported using one of following approaches: random number tables, computer‐generated random numbers
B ‐ does not specify one of the adequate methods outlined in (A) but only mentioned 'random'
C ‐ other methods of allocation that appear to be biased
Adequacy of the allocation concealment process
A ‐ adequate measures to conceal allocations, the key is the person who generate the allocation sequence do not recruit and allocate the participants, such as central randomization; serially numbered, opaque, sealed envelopes; or another description that contains convincing elements of concealment
B ‐ unclearly concealed trials in which the author does not report an allocation concealment approach at all
C ‐ inadequately concealed allocation that reports an approach that does not fall into one of the categories in (A)
D ‐ does not conceal allocation
Potential for attrition bias after allocation
A ‐ trials where an intention‐to‐treat analysis is possible and few losses to follow up are noted
B ‐ trials which report exclusions (as listed in (A) but exclusions were less than 10%)
C ‐ no reporting on exclusions or exclusions of at least 10%, or wide differences in exclusions between groups
Level of masking
A ‐ blinding of patients (yes/no/unclear)
B ‐ blinding of caregivers (yes/no/unclear)
C ‐ blinding of outcome assessment (yes/no/unclear)
All of the quality issues will be reported in the 'Characteristic of included studies table'.
Based on these criteria, studies will be broadly subdivided into the following three categories
A ‐ all quality criteria met: low risk of bias
B ‐ one or more of the quality criteria only partly met: moderate risk of bias
C ‐ one or more criteria not met: high risk of bias
Data extraction and management
Two review authors (YZ, ZX) will independently extract and cross‐check data for each trial. Discrepancies will be settled by discussion. If necessary, the trial authors will be contacted for clarification.
Data analysis
We will analyze the data using Review Manager 4.2. Outcomes from the intention‐to‐treat (ITT) will be analyzed. We will perform a pooled analysis based on clinical heterogeneity. Tests for homogeneity will be carried out using a standard Chi square test with significance being set at P < 0.1. I‐square (I2) will be used to estimate total variation across studies due to heterogeneity rather than chance in percentage, less than 25% will be considered as low level heterogeneity; 25% to 50% as moderate level, and higher than 50% as high level heterogeneity (Higgins 2003). If the trials have statistical homogeneity, the fixed‐effect model will be used for combination analysis. If statistical heterogeneity is found but without clinical heterogeneity, the random‐effects model will by used for the pooled data. If significant methodological heterogeneity is found only, we will perform the sensitivity analysis described below. The Mantel‐Haenszel relative risk (RR) with 95% confidence intervals (CI) will be used for dichotomous outcomes and mean differences (MD) or standardized mean difference (SMD) will be used for continuous outcomes. A level of P < 0.05 will be considered statistically significant. In the case of statistical significance, the number need to treat (NNT) will be calculated. Publication bias will be estimated by a visual inspection of a funnel plot if more than nine studies were involved in one subgroup.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis of the outcomes may include
1) disease severity of groups: non‐severe pneumonia and non‐hypoxemia; severe pneumonia or hypoxemia, based on data;
2) different types of oxygen therapy, based on the following data
‐ different oxygen concentrations with the same delivery systems differ in effect in patients with pneumonia but without severe pneumonia and hypoxemia: low concentration (< 35%); mid‐concentration (35% to 50%); high concentration (> 50%), based on data;
‐ different delivery oxygen systems with the same oxygen concentration differ in effect in patients with pneumonia but without severe pneumonia and hypoxemia, based on data;
‐ compare mechanical ventilation with non‐mechanical ventilation in patients with severe pneumonia or pneumonia with hypoxemia, based on data;
‐ compare one mechanical ventilation with another in patients with severe pneumonia or pneumonia with hypoxemia, based on data.
Sensitivity analysis
We will perform a sensitivity analysis with the aim to explore the influence of low quality studies on the results, for example, excluding the quasi‐RCTs and repeat the test, based on data.
