During general anaesthesia with tracheal intubation, fresh gas entering the breathing circuit of the anaesthesia machine has zero humidity and it is at ambient temperature, much lower than body temperature. Ventilation with dry and cool gases in this situation leads to a considerable loss of water and heat from the respiratory tract.1–4 Dehydration of the respiratory tract may lead to destruction of cilia and mucous glands, reduced mucociliary transport and thickening of secretions.1,4–8 Therefore, maintenance of airway humidity during anaesthesia is important to prevent pulmonary damage, such as reduced residual capacity, decreased pulmonary compliance, increased pulmonary shunt, hypoxaemia and atelectasis.4,6,9 The gases that are delivered to the patient during tracheal intubation with mechanical ventilation must be artificially conditioned to replace water and heat losses.10,11 An anaesthetic circle breathing system includes two sources of humidity and heat: the rebreathing of exhaled gas, which contains water and heat released by the patient; and water vapour and heat released from the carbon dioxide (CO2) absorbent in an exothermic reaction.12 The efficiency of humidity conservation in the breathing circuit of the anaesthesia workstation depends on the fresh gas flow (FGF) rate. Lower FGFs result in more rebreathing of exhaled gases and a consequent higher temperature and humidity of the inhaled gases in adults.9,13–17
A heat and moisture exchanger (HME) is a device that further heats and humidifies the inhaled gases during anaesthesia.14,16–20 HMEs operate passively by storing heat and moisture from the patient's exhaled gases and releasing these factors to the inhaled gases. Some anaesthesia machines are equipped with an active warming plate in the anaesthesia breathing circuit designed to prevent accumulation of humidity in the breathing circuit and flow sensors, and this also helps to increase the temperature and moisture of the inspired gas.9,18–20
Literature data5,6,10 and a review on the study participants11 proposed that an appropriate minimum target for inhaled gases absolute humidity (IGAH) is 20 mgH2O l−1 for short-duration use in general anaesthesia, and 30 mgH2O l−1 for long-duration use in intensive care to avoid respiratory tract dehydration. The duration of tracheal intubation is much shorter during anaesthesia than during intensive care. A systematic review and meta-analysis of randomised controlled trials (RCTs) comparing the effects of different FGFs on IGAH through a circle rebreathing system with or without an HME has not been performed yet. Therefore, there is still a lack of strong evidence whether different FGFs without and with an HME can provide IGAH levels of 20 and 30 mgH2O l−1, respectively, during general anaesthesia and intensive care.
We performed a systematic review and meta-analysis of RCTs whose aim was to compare the effects of different FGFs on IGAH levels in a rebreathing closed circuit CO2 absorbing mechanical ventilation system with or without an HME in intubated adult patients undergoing surgery under general anaesthesia.
The Cochrane Handbook for Intervention Reviews21 guided our choice of methods. Our reporting adheres to the Preferred Reporting Items for Systematic Reviews and Meta-analyses.22
Protocol and registration
The protocol for this meta-analysis was not registered in a public registry.
Criteria for considering studies for this review
We only included RCTs or quasi-RCTs that compared different FGF rates on IGAH levels. We included surgical adult patients (≥18-year old) undergoing general anaesthesia with tracheal intubation who received mechanical ventilation through an anaesthetic circle rebreathing system with a soda lime canister with or without an HME. We defined minimal FGF from 0.25 to 0.5 l min−1, low FGF from 0.6 to 1.0 l min−1, and high FGF at least 2 l min−1. We considered any type of HME (e.g. hygroscopic or hydrophobic).
Data source and searches
We searched the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effectiveness to identify whether any relevant systematic reviews existed. We performed a systematic search in the US National Library of Medicine (PubMed, from 1966 to January 2017), Excerpta Medica Database (EMBASE, from 1974 to January 2017), Cochrane Central Register of Controlled Trials (CENTRAL, until January 2017), the Latin American and Caribbean Health Sciences Literature Database (Literatura Latino-Americana e do Caribe em Ciências de Saúde; LILACS, from 1982 to January 2017), and Scientific Electronic Library Online (SciELO), from 1997 to January 2017 using medical subject heading (MeSH) terms and text words, including an exhaustive list of synonyms (Supplemental Digital Content 1, http://links.lww.com/EJA/A117). The last date was 31st January 2017.
Selection of studies and data extraction
Two reviewers (MGB and YH) independently screened all titles and abstracts identified by the literature search, obtained full-text articles of all potentially eligible studies and evaluated these studies for eligibility criteria. Three reviewers (JRCB, MB and LGB) manually reviewed the references of each paper, and related articles were included. There were no restrictions on language or year of publication. We used translation services at our institution when necessary. The reviewers independently extracted the following data using a prestandardised data extraction form: characteristics of the study design; participants; and IGAH data. Studies were excluded if they met any of the following criteria: no report of randomisation in the study design; focused on mechanically ventilated patients in intensive care unit; or focused on specific paediatric age groups.
Risk of bias assessment
The risk of bias approach for Cochrane reviews23 was used to assess study quality. Two authors (RED and MGB) independently used the following five separate criteria without blinding to authorship or journal of publication: random sequence generation; allocation concealment; blinding; incomplete outcome data; and selective outcome reporting. Reviewers resolved disagreements for eligibility decisions, bias risk assessment and data abstraction through discussion with third party adjudication when necessary. We made all reasonable efforts to contact the authors of the studies that published IGAH values in figures to obtain suitable IGAH data as means ± SD.
Certainty of evidence
Two reviewers (RED and JRCB) used the grading of recommendations assessment, development and evaluation (GRADE) methodology to rate the certainty of the evidence for each outcome as high, moderate, low or very low.24 Detailed GRADE guidance was used to assess overall risk of bias,25 imprecision,26 inconsistency,27 indirectness28 and publication bias,29 and results are summarised in an evidence profile.
Measures of treatment effect and heterogeneity
Review Manager provided the software for all analyses (version 5.3; Nordic Cochrane Centre, Denmark). We performed the χ2 test for subgroup differences and set the P value < 0.05. All calculations required knowledge of the means and SD for the compared IGAH data. The effect size is expressed as the mean differences and corresponding 95% confidence interval (CI). A random-effects model30 was used for all calculations to account for anticipated heterogeneity. We assessed variability in results across studies using the I2 statistic and a P value < 0.10 for the χ2 test of heterogeneity.
We performed the following subgroup analyses for the primary outcomes:
- The comparative effects of different FGF rates on IGAH, for example, minimal (≤0.5 l min−1) versus low (0.6 to 1.0 l min−1), minimal versus high (≥2 l min−1) and low versus high;
- The comparative effects of an HME in the breathing circuit on IGAH according to the FGF rate.
We also performed subgroup analyses for the secondary outcome: the effects of different times, for example, 60 and 120 min after connection of the patient to the breathing circuit on IGAH level.
Selection of titles
Our search strategy identified 6432 unique citations. We assessed the full-text versions of 56 relevant citations based on title and abstract screening, and we included 10 unique publications and excluded 46 studies (Fig. 1).
The 10 studies9,13,14,16,17,18–20,31,33 included in the meta-analysis contained a total of 527 participants who completed the trials (Table 1). Three trials were conducted in Brazil,19,20,31 two trials were conducted in Sweden14,16 and in Japan,18,32 and one trial was conducted in Turkey,9 in Germany13 and in Taiwan.17 The sample size of the studies ranged from 2120 to 9016 adult patients. The anaesthesia workstations in five studies14,16,17,18,32 had a standard breathing circuit. The exhaled gases in the breathing system of these machines move in the expiratory limb and cross the soda lime once before mixing with the cold and dry FGF. The plunger pulls the mixed gases to fill the ventilator. The inspiratory valve opens, and the ventilator's plunger sends the gaseous mixture to the inspiratory limb of the respiratory circuit. The anaesthesia workstations in two studies9,31 (Cato and Cicero, respectively, from Dräger Medical, Lübeck, Germany) had a built-in warming plate in the breathing circuit, and the mixed gases passed through the CO2 absorber twice during a breath. The anaesthesia workstations in two studies19,20 (Primus and Fabius GS Premium, respectively, from Dräger Medical, Lübeck, Germany) had a built-in warming plate in the breathing circuit. The FGF passed through the CO2 absorber before mixing with the exhaled gases in the breathing circuit of the anaesthesia machine (Sulla 808 V, Dräger Medical, Lübeck, Germany) in one study.13 The authors in another study18 compared two anaesthesia workstations: one workstation with a built-in warming plate in the breathing circuit with the mixed gases passing through the CO2 absorber twice during each breath (Cato Dräger Medical, Lübeck, Germany) and the other workstation with a standard breathing circuit (Aestiva 5, Datex-Ohmeda, Helsinki, Finland). Nevertheless, this study was considered as two different studies because of the fact two anaesthesia workstations were used in different populations.
An IGAH minimum of 20 mgH2O l−1 was attained in all studies with minimal FGF at 60 and 120 min after the connection of the breathing circuit to the patients.17,18,31 Similarly, an IGAH at least 20 mgH2O l−1 was achieved in all studies with low FGF at 120 min after the connection of the breathing circuit to the patients,9,13,14,16,18–20 except one study18 in which the authors used an anaesthesia workstation with a conventional breathing circuit (Aestiva). However, an IGAH minimum was not attained with low FGF in some studies at 60 min.9,13,18,19 Higher FGFs of 4 to 6 l min−1 did not attain the minimum target for moisture output of the IGAH at the different times in all studies included in the review.13,14,16,32 The IGAH values in all studies attained or were near 30 mgH2O l−1 when an HME was used, independent of the FGF or the time of connection of the patient to the breathing circuit. The mean temperatures of the operating rooms were 21 to 23°C in five of the included studies9,16,19,20,32 and more than 23°C in two studies.18,31 Three studies13,14,17 did not report the mean operating room temperatures (Table 1).
Assessment of risk of bias
Only one study9 adequately met all six criteria that were used to assess quality. Therefore, this study was rated as low risk of bias. Four studies19,20,31,32 satisfactorily met four criteria: generation of allocation; allocation concealment; incomplete outcome data; and selective reporting. Five studies13,14,16,17,20 met only two criteria: incomplete outcome data and selective reporting. A possibly important limitation with respect to risk of bias was a lack of blinding for personnel and outcome assessors in three studies.19,20,31 Follow-up was largely satisfactory in all studies (Fig. 2).
Grading of recommendations assessment, development and evaluation evidence profile
According to the GRADE evidence profile, the effects of different FGFs on the IGAH in the subcategory 120 min showed low quality of evidence in all subgroup analyses, except in the subgroup low flow versus low flow with an HME that showed very low quality of evidence (Table 2).
Effects of different fresh gas flow rates on inhaled gases absolute humidity according to the connection time of the patient to the breathing circuit
Minimal fresh gas flow versus low fresh gas flow
There was a statistically significant difference favouring minimal FGF compared with low FGF for IGAH in the subcategory 120 min [mean differences 2.51 (95% CI: 0.32 to 4.70), P = 0.02, I2 = 6%; three studies with 48 patients]. However, we did not find significant differences between both studied groups in the subcategory 60 min [mean differences 2.95 (95% CI: −0.95 to 6.84), P = 0.14, I2 = 75%; three studies with 48 patients; Fig. 3].
Minimal fresh gas flow versus high fresh gas flow
Meta-analysis was not possible in all subcategories because of the absence of a greater number of studies. Only one study17 reported that minimal FGF (0.25 l min−1) compared with high FGF (3 l min−1) produced significantly higher IGAH (22.1 ± 1.9 mgH2O l−1 versus 19.3 ± 2.5 mgH2O l−1) after 120 min of tracheal intubation.
Low fresh gas flow versus high fresh gas flow
There was a statistically significant difference favouring low FGF compared with high FGF for IGAH in the subcategory 120 min for FGF from 3 l min−1 to 6 l min−1 [mean differences 7.19 (95% CI: 4.53 to 9.86), P < 0.001, I2 = 96%; three studies with 102 patients; Fig. 4]. Meta-analysis was not possible in the remaining subcategories because of the absence of a greater number of studies. Only one study14 reported a statistically significant difference between IGAH favouring low FGF compared with high FGF of 5 l min−1 in the subcategory 60 min. However, the same authors did not find any significant difference of IGAH between low FGF and high FGF of 2 l min−1 in the subcategory 60 min.
Effects of different fresh gas flow rates with heat and moisture exchanger on inhaled gases absolute humidity according to the connection time of the patient to the breathing circuit
Minimal fresh gas flow without a heat and moisture exchanger versus minimal fresh gas flow with a heat and moisture exchanger
There was a statistically significant difference favouring minimal FGF with an HME compared with minimal FGF without an HME for IGAH in the subcategory 120 min [mean differences 8.49 (95% CI: 1.15 to 15.84), P = 0.02, I2 = 95%; three studies with 44 patients; Fig. 5]. Meta-analysis was not possible in the subcategory 60 min because of the absence of a greater number of studies. Only one study18 reported a statistically significant difference favouring minimal FGF with an HME compared with minimal FGF without an HME for IGAH in the subcategory 60 min.
Low fresh gas flow without a heat and moisture exchanger versus low fresh gas flow with a heat and moisture exchanger
There was a statistically significant difference favouring low FGF with an HME compared with low FGF without an HME for IGAH in the subcategory 60 min [mean differences 9.87 (95% CI: 3.18 to 16.57), P = 0.04, I2 = 97%; four studies with 75 patients] and in the subcategory 120 min [mean differences 7.19 (95% CI: 3.29 to 11.10), P = 0.003, I2 = 92%; five studies with 105 patients; Fig. 6].
High fresh gas flow without a heat and moisture exchanger versus high fresh gas flow with a heat and moisture exchanger
There was a statistically significant difference favouring high FGF with an HME over high FGF without an HME for IGAH with an FGF of 2 l min−1 at 60 min [mean differences 6.46 (95% CI: 4.05 to 8.86), P < 0.001, I2 = 65%; two studies with 60 patients] and FGF of 3 l min−1 at 120 min [mean differences 12.18 (95% CI: 6.89 to 17.47), P < 0.001, I2 = 95%; two studies with 50 patients; Fig. 7]. Meta-analysis was not possible in the remaining subcategories because of the absence of a greater number of studies. One study32 reported a statistically significant difference of the IGAH between the groups favouring high FGF with an HME compared with high FGF without an HME at 120 min with FGFs of 2 and 4 l min−1. Another study16 also reported a statistically significant difference of IGAH favouring high FGF with an HME compared with high FGF without an HME at 120 min with FGF of 6 l min−1.
Minimal fresh gas flow with a heat and moisture exchanger versus low fresh gas flow with a heat and moisture exchanger
Meta-analysis was not possible in all subcategories because of the absence of a greater number of studies. Only one study18 reported no statistically significant difference in the IGAH between minimal FGF with an HME and low FGF with an HME in the subcategories 60 and 120 min.
Low fresh gas flow with a heat and moisture exchanger versus high fresh gas flow with a heat and moisture exchanger
Meta-analysis was not possible in all subcategories because of the absence of a greater number of studies. One study14 reported no significant differences in the IGAH in all groups with an HME between low FGF and high FGF of 2 or 5 l min−1 at 60 min.
Our systematic review of existing RCTs reveals that: an IGAH minimum of 20 mgH2O l−1 was always attained with minimal FGF independent of the time of connection of the breathing circuit to the patients, but not with low or high FGFs; and the addition of an HME in the breathing circuit increases IGAH, with values which attained or were near 30 mg H2O l−1 independent of the FGF or the time of connection of the patient to the breathing circuit. In addition, our meta-analyses reveal with low-quality evidence that: the IGAH is higher with minimal FGF than with low FGF, but only after a relatively long delay; the IGAH obtained with low FGF is higher than that obtained with high FGFs; and the insertion of an HME into the breathing circuit increases the IGAH in all FGFs and times.
The circle breathing circuit with low FGF permits a higher rebreathing of exhaled gases during general anaesthesia. The expired CO2 reacts with the CO2 absorber, in an exothermic reaction, and two moles of water and 14 kcal of heat are liberated from each mole of CO2 absorbed.12 A higher humidity of the inhaled gases is expected with minimal FGF compared with low FGF and low FGF compared to high FGF. Our meta-analysis confirmed these expectations.
Our review demonstrated that higher IGAH occurred with lower FGFs after a relatively long delay. On the other hand, lower IGAH occurred with high FGFs especially with FGF more than 3 l min-1 that did not attain the minimum target for moisture output of the inhaled gases.13,14,16,32
Some authors19,21 related a large difference (approximately 8°C) between operating room temperatures and anaesthesia workstation outlet inspiratory limb gas temperatures. The authors reported that this factor caused water condensation in the inspiratory limb of the breathing circuit that was absorbed by the gases and resulted in a higher IGAH over time. Therefore, the breathing system itself worked as a moisture exchanger. Notably, the corrugated tubes of the breathing circuits have low thermal insulation materials.
Some studies used old anaesthesia machines with a conventional circle breathing circuit.14,16,17,32 Modern anaesthesia workstations, such as Dräger Primus and Dräger Fabius GS Premium, have a built-in warming plate to heat the breathing circuit and to avoid water condensation at the anaesthesia machine.19,20 Other anaesthesia workstations, such as Dräger Cato and Dräger Cicero, also have a built-in warming plate, and the exhaled gases pass through the CO2 absorber before and after mixing with the FGF pass through the CO2 absorber, i.e. twice per breath.9,18,31 It may be expected that the inhaled gases coming from these anaesthesia workstations are warmer and have a higher humidity than anaesthesia machines that use a conventional breathing circuit. Only one study18 compared the IGAH from anaesthesia machines with different breathing circuit designs (Dräger Cato and Aestiva/5 Datex-Ohmeda) using minimal or low FGF with or without an HME. These authors observed that the IGAH from the Cato machine was significantly higher than the Aestiva machine with minimal and low FGF with or without an HME. These findings are consistent with the designs of the breathing circuits of the Cato and Aestiva workstations.
Williams et al.4 demonstrated that lower IGAH values could be tolerated for short periods of time without causing dysfunction of the tracheobronchial epithelia. Therefore, the additional use of an HME in the breathing circuit during anaesthesia is probably not required when the minimum IGAH value is provided by the anaesthesia workstation, which was emphasised previously in a review on HME use in anaesthesia and intensive care.11 Our systematic review showed that the minimum target for moisture output of the IGAH at the different times was always attained with minimal FGF but not with low flow or, especially, high flows.
Williams et al.4 also demonstrated that critically ill patients are less tolerant to water mass and thermal challenges to their airway mucosa. These patients require higher IGAH. Therefore, the use of an HME in the breathing circuit in a low flow and specially in a high-flow anaesthesia machine is indicated for surgical patients with respiratory tract dysfunction or patients who require long-term postoperative mechanical ventilation.11 An HME device that properly humidifies and warms the inhaled gases early in the surgical procedure may be advantageous, which was demonstrated in some studies.14,17,32
Our meta-analysis demonstrated that IGAH increased with the insertion of an HME in the breathing circuit at all FGFs. It was not possible to verify the correlation between the FGF rate and HME efficiency by meta-analysis. However, one study reported no significant differences in the IGAH between low FGF and high FGF of 2 or 5 l min−1 in all groups with an HME.14 One study also demonstrated no significant difference in the IGAH between minimal and high FGF (3 l min−1) with an HME.17 Therefore, the FGF rate seems to have no significant correlation with HME efficiency in adult patients. There is no minimum requirement for humidification performance in the current standards for HMEs (ISO 9360-1 : 2000).33 The American Association of Respiratory Care34 set an IGAH minimum of 30 mgH2O l−1, whereas the international standard (ISO 8185 : 2007)35 set an IGAH minimum of 33 mgH2O l−1 for the well tolerated and effective performance of respiratory humidification systems for long-term mechanical ventilation in patients whose upper airways have been bypassed by a tracheal tube. However, IGAH of 33 mgH2O l-1 is above the level that can normally be delivered by HMEs. Our review and other authors36,37 confirmed these expectations.
Few studies investigated the postoperative respiratory tract outcomes of the patients. One study9 reported the effects of low flow and high flow (3 l min−1) on mucociliary clearance (using saccharin transit time) and pulmonary function in surgical patients undergoing general anaesthesia using a Dräger Cato anaesthesia workstation. The postoperative forced vital capacity and forced expiratory volume in 1 s were significantly lower, and the saccharin clearance time was significantly longer, in the high-flow group compared with the low-flow group. The authors suggested that respiratory function and mucociliary clearance were better preserved in low-flow anaesthesia. Another study38 used the Dräger Sulla 800 V anaesthesia machine, in which the FGF passed through the soda lime canister into the breathing circuit before mixing with the exhaled gases. The authors did not find significant differences between high-flow ventilation (3 l min−1) with or without an HME on bronchial mucus transport velocity (using albumin microspheres labelled with technetium Tc99m) in surgical patients undergoing general anaesthesia. However, the IGAH was not recorded in this study.
Strengths and limitations
The strengths of our review include a comprehensive search, assessments of eligibility and risk of bias, and data abstraction independently and in duplicate. The assessment of risk of bias included a sensitivity analysis that addressed patients lost to follow-up. We also used the GRADE approach to rate the certainty of evidence for each outcome. Despite the heterogeneity and small number of studies, the meta-analyses showed consistent results that strongly reinforce the findings of our systematic review considering that both showed similar results and do highlight the possibility that minimal FGF determines high IGAH levels compared with low flow, a possibility that until now showed divergent results from RCTs18,31 and, therefore, needs consideration for clinical practice.
There are some limitations to our review and meta-analyses. First, the review is limited by a paucity of studies comparing different FGFs with and without an HME. Thus, we were not able to assess publication bias because there were less than 10 eligible studies addressing the same outcome in a meta-analysis. Second, there was a high rate of heterogeneity between the studies because of the different breathing circuits from the anaesthesia workstations. We anticipated this heterogeneity and used a random-effects model for all of our calculations. Third, three studies13,14,17 did not report the operating room temperatures, whereas in two studies the operating room temperatures were more than 23°C.18,31 Most studies included in the review reported operating room temperatures of 21 to 22°C, which are suitable ambient temperatures to maintain adequate comfort for the surgeons. Some studies found a significant and positive correlation between the operating room and inhaled gas temperatures.19,20 Higher gas temperatures increase IGAH, and the higher operating room temperatures reported in some studies18,31 may have influenced the IGAH data. Fourth, some studies were excluded from the quantitative analyses because the IGAH data were reported in forms other than by means and SD.
Implications for clinical practice
According to the results of our current systematic review with meta-analysis, the recommendations for how to manage FGF and the use of an HME based on RCTs to obtain adequate IGAH levels in intubated adult patients undergoing general anaesthesia are: an HME should be used with low flow or high flow because it preserves minimum levels of the IGAH regardless of the FGF rate administered; and an HME with minimal FGF is not necessary considering that an HME adds cost and minimal flow provides the same benefit, with an appropriate minimum target of the IGAH thought to reduce the risk of dehydration of airways.
Implications for research
Further research is needed to compare the IGAH between modern anaesthesia workstations with different FGF rates and with or without an HME in the breathing circuit and investigate postoperative respiratory tract outcomes of the patients.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
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