Perioperative Amino Acid Infusion for Preventing Hypothermia and Improving Clinical Outcomes During Surgery Under General Anesthesia: A Systematic Review and Meta-analysis : Anesthesia & Analgesia

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Anesthetic Clinical Pharmacology

Perioperative Amino Acid Infusion for Preventing Hypothermia and Improving Clinical Outcomes During Surgery Under General Anesthesia: A Systematic Review and Meta-analysis

Aoki, Yoshitaka MD; Aoshima, Yukie MD, PhD; Atsumi, Kazuyuki MD; Kaminaka, Ryo MD; Nakau, Rintaro MD; Yanagida, Kyoko MD; Kora, Makiko MD; Fujii, Shunsuke MD; Yokoyama, Junichiro MD

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Anesthesia & Analgesia 125(3):p 793-802, September 2017. | DOI: 10.1213/ANE.0000000000002278


Mild hypothermia during general anesthesia1 can cause adverse outcomes including myocardial ischemia,2 increased risk of surgical wound infection,3 extended hospitalization,2 and coagulopathy.4 Perioperative amino acid (AA) infusion prevents hypothermia during general anesthesia from stimulating energy expenditure at rest and increasing the metabolic rate to levels above the basal state;5 nevertheless, the underlying mechanism is not fully understood.

Several studies have reported that AA infusion increases patient body temperature.5–7 Most of these, however, are small in sample size, and may lack power to explore whether AA infusions improve clinical outcomes. To that end, a recent systematic review of AA infusion during the perioperative period conducted in 20148 compared temperature changes in surgical patients who received AA infusions to crystalloid infusions. In comparison to crystalloid infusions, they found that AA infusions were effective at reducing heat loss.

One potential limitation of this meta-analysis was that it did not use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.9 The GRADE system provides a tool to rate the quality of evidence over several studies for a given clinical outcome. Using this tool, the quality of the available evidence can be described in terms of methodologic flaws, consistency across different studies, generalizability, and treatment effectiveness.

This aim of this study was to assess the quality of evidence that AA infusions increase patient body temperature during general anesthesia and improve clinical outcomes using the GRADE system.


This manuscript adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement except that we could not complete the preregistration of our protocol. We also used the principles of the GRADE system9 and the Cochrane methodology.10

Study Inclusion Criteria

Types of Studies.

Randomized controlled trials of perioperative AA infusion versus placebos that reported on patient body temperature and other outcomes were included.

Types of Participants.

Participants having undergone any surgical operation under general or combined general/epidural anesthesia were research subjects. We excluded participants undergoing cardiac surgery with cardiopulmonary bypass because cardiopulmonary bypass influences body temperature greatly. We also excluded participants undergoing spinal anesthesia because of a different mechanism of hypothermia.1

Types of Interventions and Comparisons.

We investigated the effectiveness of AA infusion versus placebo to prevent hypothermia. Placebo was used to describe no infusion or nutrient-free infusion preparation (eg, crystalloid or saline). We excluded cases with nutrient-rich infusion preparation because this makes an assessment of AA infusion efficacy more difficult. However, because selected preparations of crystalloids contain small amounts of glucose, placebo was defined as a preparation containing 5% glucose or less. We included any type of AA infusion preparation and any timing and rate of AA infusion as long as it was conducted in the perioperative period.

Types of Outcome Measures.

We included patients’ clinical outcomes but excluded data related to biochemical markers and catecholamine blood concentrations.

The primary outcome measurement was difference in body temperature during the perioperative period. Secondary outcomes were as follows:

  • Shivering frequency
  • Blood loss volume
  • Postoperative intubation time
  • Hospitalization period

We defined “body temperature difference” as the difference in body temperature before and after perioperative AA infusion. When multiple body temperature data were present, we defined the difference as the first body temperature subtracted from the final body temperature. In addition, if multiple data for body temperature differences measured with the same sensor were present, we gave priority to the primary outcome in each study. We also managed other secondary outcomes in the same way.

Search Strategy

We electronically searched the MEDLINE (PubMed), the Cochrane Central Register of Controlled Trials, and the Igaku Chuo Zasshi (Japana Centra Revuo Medicina) on November 19, 2015. We used the search strategies (Supplemental Digital Content 1, Table, referring to the Cochrane Handbook for Systematic Reviews of Interventions.10 A manual search of reference lists was also conducted. We did not apply any language restrictions.

Data Collection

We selected all studies extracted using the search methods. Two authors independently screened these studies from titles and abstracts and assessed them according to our inclusion and exclusion criteria. Data elements were extracted to confirm study eligibility, study design, patient demographics, performed interventions, outcomes of interest, statistical methods, and study results. When questions arose regarding data elements, we attempted to contact original authors provide clarity.

Assessment Risk of Bias With Included Studies

The quality of the included studies was independently assessed by 2 authors according to the Cochrane methodology.10 In case of disagreement, a third author made the final decision.

We used the Cochrane “risk of bias” tool in RevMan 5.3 (Copenhagen: the Nordic Cochrane Centre, the Cochrane Collaboration, 2014) to assess the extent of potential bias in the included studies. We considered the following domains:

  1. Random sequence generation (selection bias)
  2. Allocation concealment (selection bias)
  3. Blinding of participants and personnel (performance bias)
  4. Blinding of outcome assessment (detection bias)
  5. Incomplete outcome data (attrition bias)
  6. Selective reporting (reporting bias)
  7. Other biases

Each domain was classified as low, unclear, or high risk of bias, according to the Cochrane methodology described above. We created a “risk of bias” summary, which details all of the judgments made for all included studies in this review.

We also used the GRADEpro to create a “Summary of findings (Sof)” table. Using the Sof table, we presented the results in an uncomplicated tabular format including the anticipated absolute effects, relative effect, number of participants and number of studies, and the quality of evidence related to each outcome. The quality of evidence was classified as high, moderate, low, and very low for each outcome on the basis of the risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Data Synthesis and Statistical Analysis

We used RevMan 5.3 to conduct our statistical analysis. The random effect model was used for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect. Forest plots were constructed to graphically display the results of the individual studies and pooled estimates of effect. The pooled results of dichotomous outcomes were expressed as risk ratio with 95% confidence interval (CI). For continuous variables, a pooled estimate of treatment effect was calculated as the mean difference (MD) or the standardized mean difference (SMD) and 95% CI. The heterogeneity across studies was tested using the I2 statistic (values of 0%–25%, 25%–50%, 50%–75%, and 75%–100% were considered to represent absent, low, moderate, and high heterogeneity, respectively). When there were 10 or more studies in a meta-analysis, we investigated reporting bias (publication bias) using a funnel plot. We visually assessed funnel plot asymmetry.

Subgroup Analysis

When we identified heterogeneity that was moderate or greater, we conducted a subgroup analysis to investigate the cause of heterogeneity. As for types of AA infusion preparation, the subgroup analysis was conducted for the primary outcome.


Search Results

Figure 1.:
PRISMA flow diagram. PRISMA indicates Preferred Reporting Items for Systematic Reviews and Meta-analyses.

We identified 250 studies from the MEDLINE search, 29 studies from the Cochrane Central Register of Controlled Trials search, and 19 studies from Japana Centra Revuo Medicina on November 19, 2015. Manual searching of reference lists did not find any extra publications. Our electronic database search identified a total of 279 studies, 258 of which were excluded because of our aforementioned inclusion criteria. After a review of full-text articles, an additional 7 studies were excluded for the reason described in Figure 1. Therefore, 14 studies remained in our systematic review (Figure 1).

Study Design and Characteristics of Included Studies

The 14 included studies are shown in Table 1.7,11–23

Table 1.:
Characteristics of Included Studies

A total of 626 participants were included; 327 participants had received AA infusion and formed the intervention group, and 299 participants had been given a placebo and formed the control group. Among the 14 included studies, 5 studies had multiple groups other than with or without AA infusion.11,14,16,18,19 For some of the 5 studies, we were able to assign the participants to 1 group or the other by contacting the authors.11,14 We could not contact the authors of 2 studies16,18; hence, we used the data from each arm separately for analysis. The Kamitani study16 included 4 groups divided not only according to whether they received AA or a SOLITA-T No.1 infusion but also according to the length of surgery time, but this did not prevent us from differentiating between AA and placebo cases. Sahin and Aypar18 also had 4 groups: 1 group received isoflurane and a placebo, 1 group received propofol and a placebo, 1 group received isoflurane and AA, and the last group received propofol and AA. The remaining study19 also included 4 groups; however, the results were organized into 2 groups according to whether or not AA infusion was received.

Risk of Bias in Included Studies

Figure 2.:
Risk of bias summary. Green circle indicates low risk of bias, yellow circle indicates unclear risk, and red circle indicates high risk (as with risk of bias graph).

The risk of bias assessments for included studies is summarized in Figure 2. All domains were “low risk of bias” in 2 studies7,15; however, the remaining studies had many domains that lacked clarity.

Effects of Interventions

Table 2.:
Summary of Findings

See Sofs for the main comparison (Table 2). We judged the quality of evidence as body temperature difference, blood loss volume, and hospitalization period as low; shivering frequency as very low; and postoperative intubation time as moderate. We described the reason for downgrading the quality of evidence in the footnote of Table 2.

Primary Outcome: Body Temperature Difference

All 14 studies,7,11–23 including 626 participants, reported the difference in body temperature as outcomes. AA infusion increased body temperature by MD of +0.46°C and showed high heterogeneity (95% CI, 0.31–0.62; I2 = 87%; Figure 3).

Figure 3.:
Forest plot of body temperature difference. CI indicates confidence interval.

The start and stop timings for body temperature measurements were different in each study. We expressed the start timing for measurement as “zero point” and the stop timing as “end point” in Table 1. We defined “body temperature difference” as the amount of difference from 0 to end point.

Figure 4.:
Forest plot of body temperature difference. Subgroup: types of amino acid infusion preparation. CI indicates confidence interval.

In consideration of the high statistical heterogeneity (I2 = 87%) obtained for the analysis, we performed a preplanned subgroup analysis according to types of AA infusion preparation (amiparen, vamin, traumamine, teruamino, novamin, or not reported) used in each study. Subgroup analysis that classified types of AA infusion preparation did not reveal any difference between groups (P = .15; Figure 4).

Secondary Outcomes

Shivering Frequency.

Seven studies,13–15,18,20–22 including 248 participants, reported shivering frequency in the perioperative period. Five13,14,20–22 of the 7 studies reported only on the number of patients who experienced shivering. One study15 reported the incidence of shivering according to a “shivering grade” (none, mild, moderate, and severe). Hence, we judged that shivering had occurred for a rating of mild or more. Another study18 reported the incidence of shivering using a “grading of shivering,” in which shivering degree was assessed as 1 of 5 levels (0, 1, 2, 3, and 4); hence, we judged that shivering had occurred for a rating of grade 1 or more. AA infusion decreased shivering frequency by risk ratio of 0.34 and showed high heterogeneity (95% CI, 0.12–0.94; I2 = 76%; Supplemental Digital Content 2, Figure 1,

Blood Loss Volume.

Five studies,7,15,17,21,22 including 274 participants, reported on this outcome. One of the 5 studies22 reported blood loss volume using the unit “gram,” and the remaining 4 studies7,15,17,21 reported using the unit “mL.” Hence, we integrated the results using SMD. AA infusion reduced blood loss volume by SMD of −0.20 with the absence of heterogeneity (95% CI, −0.44 to 0.04; I2 = 0%; Supplemental Digital Content 3, Figure 2,

Postoperative Intubation Time.

Two studies,7,17 including 158 participants, reported on this outcome. Two studies included patients undergoing off-pump coronary artery bypass. In the Moriyama study,17 patients were extubated when fully awake and able to maintain an acceptable respiratory rate and depth after rewarming to 37.5°C in the intensive care unit. In the Umenai study,7 patients were extubated in the operating room or intensive care unit when they fulfilled the extubation criteria set in advance. AA infusion shortened postoperative intubation time by MD of −125 minutes and moderate heterogeneity (95% CI, −210 to −38.8; I2 = 54%; Supplemental Digital Content 4, Figure 3,

Hospitalization Period.

Three studies,7,14,21 including 230 participants, reported on this outcome. These 3 studies determined their discharge criteria and compared AA infusion with placebo. AA infusion shortened hospitalization period by MD of −1.81 days with no heterogeneity (95% CI, −2.07 to −1.55; I2 = 0%; Supplemental Digital Content 5, Figure 4,

Assessment of Reporting Bias

The funnel plot is graphically presented in Supplemental Digital Content 6, Figure 5, The funnel plot revealed symmetry, indicating no reporting bias.


The aim of this meta-analysis was to explore the effectiveness of an AA infusion in treating hypothermia in patients under general anesthesia using the GRADE system. We found that AA infusions administered in the perioperative period led to a small increase in patient body temperature, a decrease in the frequency of shivering, a decrease in the time to extubation, and a decrease in the duration of hospitalization. However, the quality of evidence ranged from very low to moderate, and the confidence in the effect estimate was limited according to GRADE Working Group grades of evidence (Table 2). Our analysis suggested that perioperative AA infusion is useful in treating hypothermia; however, because of the low quality of evidence, our results should be interpreted with caution.

Although we found that AA infusions led to a +0.46°C increase in temperature, we suggest that this small difference is of clinical significance. This may be particularly true in instances where it is difficult to increase a patient’s body temperature using conventional perioperative warming therapies. For example, in a previous study,24 researchers found that 3 hours of warming with an underbody resistive warming system led to mean +0.1 (SD 1.08)°C and that with an upper body warming system led to mean +0.4 (SD 0.98)°C in patient body temperature during abdominal surgery. Although we cannot be convinced because the warming time and kind of surgery are different, AA infusion may have a similar effect as conventional warming systems and may serve as a viable alternative.

The result of the subgroup analysis on the primary outcome is shown in Figure 4. The heterogeneity between the subgroups was moderate, and no difference was observed. Based on the results obtained from each subgroup, we observed that amiparen and vamin groups showed increased body temperature in patients with AA infusion, which was similar to that of the overall results. The number of studies in each subgroup is small in the other subgroups; therefore, interpretation is difficult. Mizobe25 reported that the degree of increase in body temperature varies according to the AA composition; therefore, we had performed subgroup analysis in this review. Because each subgroup had a small number of studies, it may be necessary to focus on types of preparation of AA infusion in future research.

In other clinical outcomes, this review showed a decrease in shivering frequency, although the quality of the evidence was very low. Perioperative shivering is believed to increase oxygen consumption by 300% to 400%26 and increase the risk of hypoxemia; therefore, AA infusion may be useful in this. Next, AA infusion did not show a reduction of blood loss volume. Although excluded from this systematic review because of spinal anesthesia use, a previous study27 reported that AA infusion showed a decrease in blood loss volume. We believe additional studies may prove that AA infusion could show a reduction in blood loss volume. Finally, AA infusion shortened postoperative intubation time and hospitalization period. Another study28 reported that AAs are directly used for the synthesis of new muscle proteins. There was a possibility that patient postoperative recovery may be accelerated by the action of AAs.

We believe that AA infusion therapy is useful, and we use it in daily clinical practice. At our hospital, Amiparen is infused at a rate of 100 mL/h according to the package insert when a patient’s body temperature tends to decrease, but it is unclear whether this is the most suitable infusion method for preventing hypothermia. Although AA infusion during the perioperative period has been studied from various aspects,25 there are also many facts that are not known.

Although we had limited AA infusion in this review, we are unaware of its superiority or inferiority compared with other nutrients. For example, Mizobe et al29 had suggested the use of fructose for preventing hypothermia; therefore, other nutrients may also be useful. At present, a study on “Intravenous nutrients for preventing inadvertent perioperative hypothermia” by Warttig et al30 is ongoing in the Cochrane library. We look forward to the results of this Cochrane review.

We acknowledge that there are several limitations in this review. First, the content of each study is inconsistent. There was variation in the AA infusion method (eg, infusion volume, start timing, rate). For body temperature measurements, the start and end points of measurement and the measurement sites were different for each study. The presentation of body temperature measurement differed for each study, and in some studies, it was only expressed in figures. Furthermore, the body temperature difference is thought to be influenced by the type of surgery, but the surgery type was not consistent. These differences are presumed to be the cause of reliability variation of body temperature measurements. Second, there were variations in the quality of each study. Many studies did not have a preresearch protocol and, therefore, the period of follow-up was not specified. Most studies did not examine the safety and side effects of AA infusion itself. Although there are limitations as described above, we believe this study to be valid because we have shown the usefulness of the AA infusion through meta-analysis. Third, few studies have considered AA intake before surgery. Preoperative nutritional supplementation using enhanced recovery after surgery protocol has recently been performed, and the effectiveness of intraoperative AA infusion in that setting has room for consideration from the viewpoint of energy balance. Finally, we could not calculate sample size and power analysis in this study.

In summary, the results of our systematic review suggest that AA infusion in the perioperative period increases patient body temperature, decreases shivering frequency, shortens postoperative intubation time and hospitalization period; however, the quality of evidence was low because of several limitations in the GRADE system. Hence, to improve the quality of evidence, further large-scale randomized controlled trials to pay attention to the type of AA infusion preparation are required.


We thank Drs Yasuki Fujita and Takako Umenai who responded to questions on their study. We are grateful to Ms Michiko Yoshii for designing the search strategy and Dr Toshio Shimada for carefully proofreading the manuscript.


Name: Yoshitaka Aoki, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Yukie Aoshima, MD, PhD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Kazuyuki Atsumi, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Ryo Kaminaka, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Rintaro Nakau, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Kyoko Yanagida, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Makiko Kora, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Shunsuke Fujii, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

Name: Junichiro Yokoyama, MD.

Contribution: This author helped conception, design of the work, data acquisition, analysis, and interpretation, drafting of the manuscript and critically revising it for intellectual content, and final approval of the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.


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