A Cross-Sectional Survey on Nonhepatic Hyperglycemia in Intensive Care Unit, Heilongjiang Province, China

Yue Li; Zhipeng Yao; Tong Li; Hongliang Wang

doi:10.4103/jtccm.jtccm_29_20

ORIGINAL ARTICLE

Year : 2020 | Volume : 2 | Issue : 2 | Page : 36-40

A Cross-Sectional Survey on Nonhepatic Hyperglycemia in Intensive Care Unit, Heilongjiang Province, China

Yue Li, Zhipeng Yao, Tong Li, Hongliang Wang
Department of Intensive Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

Date of Submission	23-Nov-2020
Date of Acceptance	04-Dec-2020
Date of Web Publication	31-Dec-2020

Correspondence Address:
Dr. Hongliang Wang
Department of Intensive Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jtccm.jtccm_29_20

Abstract

Introduction: The importance of blood ammonia detection and nonhepatic hyperammonemia (NHH) in the treatment and prognosis of patients has been neglected clinically. The purpose of this study was to evaluate the etiology, diagnosis, treatment, and prognosis of NHH in intensive care unit adults in Heilongjiang province, China. To solve this problem, we designed a provincial-level survey of severe adult NHH, including its etiology, risk factors, incidence, prognosis, and treatment strategies. Methods: The present study refers to a cross-sectional survey of the whole province, involving five cities in Heilongjiang province. All patients who met the inclusion criteria were eligible to apply to participate in the study, which included baseline demographics, clinical presentation, and follow-up related to diagnosis and treatment. Results: The total number of patients to be recruited in this study was estimated to reach 759. All patients who met the inclusion criteria were eligible to apply to participate in the study, which included baseline demographics, clinical presentation, and follow-up related to diagnosis and treatment. Conclusion: This study is expected to provide a theoretical basis for the development of more scientific and standardized NHH diagnosis and treatment methods. Ethics and Dissemination: Ethical approval was obtained from the ethics committee of The Second Affiliated Hospital of Harbin Medical University (registration number KY2019-184). The findings of this review will be communicated through peer-reviewed publications and scientific presentations. Trial Registration Number: ChiCTR1900026632.

Keywords: Blood ammonia level, intensive care unit, nonhepatic hyperammonemia, severe patients

How to cite this article:
Li Y, Yao Z, Li T, Wang H. A Cross-Sectional Survey on Nonhepatic Hyperglycemia in Intensive Care Unit, Heilongjiang Province, China. J Transl Crit Care Med 2020;2:36-40

How to cite this URL:
Li Y, Yao Z, Li T, Wang H. A Cross-Sectional Survey on Nonhepatic Hyperglycemia in Intensive Care Unit, Heilongjiang Province, China. J Transl Crit Care Med [serial online] 2020 [cited 2023 Mar 31];2:36-40. Available from: http://www.tccmjournal.com/text.asp?2020/2/2/36/305791

Introduction

As the main product of amino acid metabolism, ammonia can enter the brain through the blood–brain barrier when the blood ammonia is elevated, causing glial cell edema, leading to the change of consciousness and the increase in intracranial pressure in patients, forming hepatic encephalopathy, posing a serious threat to the life of patients. Blood ammonia level indicates the status of liver function and energy supply of the body, as well as affects the tricarboxylic acid cycle. Accordingly, high blood ammonia level primarily affects severe patients with insufficient energy supply or metabolism of the body. Hyperammonemia is generally considered to occur in patients with acute liver failure (ALF) or chronic liver disease (CLD), whereas it can exist in cases without basic liver disease as well; it is termed nonhepatic hyperammonemia (NHH).^[1],[2],[3] However, the importance of blood ammonia detection and NHH in the treatment and prognosis of patients has been commonly overlooked in clinical practice.

In clinical practice, blood ammonia monitoring is the first step of using blood ammonia to assess the disease. We should pay close attention to the changes of blood ammonia in patients exhibiting a high risk of blood ammonia clinically. At present, detection of ammonia arterial blood is considered to be more stable and reliable than detection of venous blood. High blood ammonia is associated with the development and mortality of severe diseases, so clinical and timely intervention is of critical significance. In his systematic review of hyperglycemia, Haberle J emphasized the importance of blood ammonia assessment and treatment and considered that the treatment of hyperglycemia should be initiated immediately after the assessment of hyperglycemia without waiting for specific diagnosis.^[4] Any delay in the timing of treatment for the identification of hyperglycemia may cause patients to worsen. Thus, patients with high blood ammonia should be given individualized and active treatment measures by complying with the blood ammonia level.

In brief, the insights into serum ammonia should be extended over traditional liver diseases or hepatic encephalopathy, and NHH should arouse sufficient attention in clinical practice. For other indicators combined (e.g., blood ammonia, lactic acid, and ketone body), patients' condition should be more comprehensively assessed. In clinical practice, the first thing is to actively monitor blood ammonia and find the increase in blood ammonia attributed to a range of reasons in a timely manner, and early intervention and treatment may critically improve the prognosis of severe patients. This study aimed to assess the etiology, diagnosis, treatment, and prognosis of NHH in intensive care unit (ICU) adults in Heilongjiang province, China. Accordingly, the results of this study are expected to provide vital information for further treatment of Chinese nonhepatic hyperemia patients.

Methods

Study design

The present study refers to a cross-sectional survey of the whole province, involving five cities in Heilongjiang province. At least one tertiary first-class hospital of each city will be selected, and the overall number of hospitals will be 10. The total number of patients to be recruited in this study was estimated to reach 759, and the calculation formula is as follows:

Formula for sample size estimation:

π = 0.7598 δ = 0.04 × 0.7598 Formula for infinite sample population:

n = 1.96² × 0.7598 × (1 - 0.7598) / (0.04 × 0.7598)²

n ≈ 759

Sampling criteria

Inclusion criteria

Patients transferred to and directly admitted to ICU in the study period
Age ≥18 year old
All patients satisfying the inclusion criteria during the investigation.

Exclusion criteria

ALF: All the following requirements are satisfied: (1) presence of hepatic encephalopathy; (2) international normalized ratio ≥1.5; (3) acute onset in 26 weeks; and (4) no cirrhosis occurrence
CLD: Cirrhosis or liver disease abiding by the international classification (9^th Edition) (ICD-9 codes)
Patients re-admitted to ICU
Patients having not signed informed consent.

Exit criteria

(1) The patient or the legal representative asks to withdraw from the trial; (2) poor compliance, unable to follow up as designed.

Analysis and Results Data collection

The present study refers to a clinical trial exhibiting provincial, multicentric, prospective, randomized, and cross-sectional characteristics. After patients were recruited, a standardized table was generated to record the relevant data [the process illustrated in [Figure 1]. By consensus, research committees were elected, and the study procedures were monitored. The investigation period ranged from 08:00 on the 1^st day to 08:00 on the 31^st day of the study.

Figure 1: This study is a multicentric, prospective, randomized, cross-sectional clinical survey in Heilongjiang province, China. Thus, a high-quality, cross-sectional survey is needed, and the process of performing this study can be found in the figure, which will be separated into three parts. ALF: Acute liver failure, CLD: Chronic liver disease, ICU: Intensive care unit

Click here to view

Patient demographics and clinical performance

Basic information
ICU diagnosis and basic blood ammonia
Acute Physiological and Chronic Health Assessment (APACHE II score), Glasgow Coma Score (GCS score), and Sequential Organ Failure Assessment (SOFA score) (highest score in 24 h)
Nutritional therapy.

Measurements and statistical analysis

Main indicators: NHH incidence, correlations between serum ammonia level and length of stay in ICU, APACHE-II, SOFA, GCS score, and prognosis
Prognostic risk factors of NHH were assessed
In NHH patients, the subgroup analysis was conducted in patients with poisoning to elucidate the correlations between NHH severity and prognosis
Statistics of the current treatment of NHH patients in China to develop a standardized clinical program.

Protection of patient rights

All patients recruited were informed, and they signed a written consent form. All information regarding patients have been kept confidential.

Discussion

Blood ammonia, as the main metabolite of amino acids in the body, critically impacts substance metabolism and biological transformation. Existing studies commonly stressed the theory of high blood ammonia and ammonia poisoning attributed to liver diseases, whereas the causes of increased blood ammonia attributed to liver diseases and the effects of high blood ammonia on other organ functions were overlooked. NHH has not aroused extensive clinical attention, and no consistent standard has been set for its early diagnosis and treatment strategy. In addition, the present situation of diagnosis and treatment of NHH in ICUs of China remains unclear. This study primarily covered several vital aspects of NHH (e.g., clinical diagnosis, condition assessment, life support and monitoring, as well as prognostic indicators). Given the findings here, the mentioned questions are hopefully to be answered, and the authors seek to propose an effective and standardized approach for subsequent NHH management for ICUs in China.

Diagnostic criteria and etiology of nonhepatic hyperammonemia

Under poor insights into NHH, inconsistent diagnostic criteria have been set. In normal scenarios, the blood ammonia level in the absence of basic liver disease is termed NHH. As revealed from a prospective study by Prado et al., in the recruited patients with severe diseases, high blood ammonia attributed to liver disease was excluded, NHH was identified in 73% of the patients, and a significant correlation was reported between blood ammonia level and patient mortality.^[3] However, because NHH patients have no history of liver disease, they are easy to be missed clinically. On the whole, severe patients have various risk factors leading to high blood ammonia (e.g., increased blood ammonia production and decreased blood ammonia clearance). Promoted production of blood ammonia is considered to be common: stress factors (e.g., urease microbial infection, pneumonia, and fever) lead to a high production of blood ammonia and gastrointestinal bleeding, steroids, and trauma increase protein breakdown and ammonia production. Reduction of blood ammonia clearance is extensively observed in acute and chronic liver failure attributed to drugs or toxins, infections, and autoimmune diseases, and the ammonia clearance ability of livers is suppressed. Salicylic acid and valproic acid are capable of damaging the mitochondrial function of hepatocytes or inhibiting the activity of the rate-limiting enzyme in the urea cycle, thereby causing dysfunction of urea synthesis and further elevation in blood ammonia. Acute renal injury and uremia can lead to decreased renal blood flow and downregulated glomerular filtration rate, as well as decreased renal urea excretion. Thus, for a considerable amount of risk factors of hyperglycemia, whether patients have hyperglycemia is worth highlighting clinically.^[5],[6]

Nonhepatic hyperammonemia in relation to critically related diseases

Blood ammonia level indicates the status of liver function and energy supply of the body, as well as exerts an effect on the tricarboxylic acid cycle. Accordingly, high blood ammonia level has a major effect on patients with severe diseases, exhibiting insufficient energy supply or metabolism for their bodies. By referencing relevant literatures, it was suggested that besides hepatic encephalopathy, studies on NHH-related severe diseases placed a primary emphasis on severe heart events and septic shock.

High blood ammonia and severe cardiac events

Overall, patients suffering from congestive heart failure show high blood ammonia and an association with reduced cardiac function. As early as 1955, a study reported that the arterial and venous blood ammonia in patients exhibiting congestive heart failure was higher than that in other patients without liver disease.^[7] Andrews et al. assessed the response of ammonia to training volumes in patients with a range of cardiac function grades. They indicated that blood ammonia in NYHA Class III patients in resting state was significantly higher than that in NYHA Class II and healthy control groups. With the increase in exercise load, the increase in blood ammonia in NYHA class III patients was more significant than that in NYHA Class II and healthy control groups.^[8] Increased blood ammonia in patients exhibiting congestive heart failure may be related to liver congestion. As suggested by other studies, elevated blood ammonia absorption due to intestinal wall hypoxia and bacterial growth majorly results in high blood ammonia uptake in patients exhibiting advanced heart failure.^[9] Ogino et al. drew a comparison on the variations of lactic acid and blood ammonia in heart failure patients and healthy people during exercise. They reported that the energy metabolism of heart failure patients underwent three stages, that is, before reaching the lactate threshold, muscles were supplied by aerobic metabolism, during which adenosine triphosphate (ATP) supply was sufficient. Blood lactic acid increases, as opposed to blood ammonia if the lactic acid threshold is reached, instead of the ammonia threshold, and the energy is supplied by aerobic metabolism and glycolysis simultaneously. If the threshold of ammonia is reached, ATP is being rapidly consumed, and blood lactic acid and blood ammonia increase simultaneously. In patients exhibiting heart failure, a simultaneous increase in blood lactic acid and ammonia indicates a reduced aerobic and anaerobic metabolic capacity of skeletal muscles.^[2] Thus, combining lactic acid and blood ammonia can determine the state of energy metabolism in patients with heart failure. Moreover, the study found that the survival rate of patients suffering from severe heart disease with reduced blood ammonia was significantly higher than that of those with sustained high blood ammonia.^[9] Accordingly, reducing blood ammonia level may help elevate the survival rate of such patients. Recently, Bing proposed the hypothesis of “the role of ammonia lowering to prevent and reverse heart failure.” Excessive cardiac load will lead to changes in ammonia balance, resulting in ammonia production exceeding its neutralized amount, whereas excessive ammonia will exert a series of downstream effects, leading to apoptosis or death of cells. The intervention treatment of excessive ammonia surplus is capable of preventing the occurrence of adverse cardiac reactions at the early phase, as well as reversing the effect of heart failure at the later phase.^[10]

Hyperammonemia and septic shock

Septic shock can easily cause multiorgan dysfunction syndrome, in which liver dysfunction may improve ammonia clearance ability and elevate blood ammonia.^[11],[12] Moreover, some factors (e.g., increased intestinal permeability attributed to infection, increased intestinal ammonia production due to gastrointestinal bleeding, and amino acid metabolism related to parenteral nutrition) may increase blood ammonia in septic shock patients.^[13] Accordingly, a question is raised that what is the effect of elevated blood ammonia on the pathophysiological process of septic shock patients. Marini and Broussard compared the reactions of wild-type and hyperglycemic mice to bacterial lipopolysaccharides. They reported that hyperammoniacal mice exhibited improved sensitivity to lipopolysaccharides. Thus, it was speculated that hyperammoniacal mice can alter the degree of inflammatory response and the sensitivity of the body to inflammatory response.^[14] Other studies reported that elevated blood ammonia can cause dysfunction of neutrophils and macrophages and weaken phagocytosis, which may eventually lead to “sepsis-” like immune paralysis.^[15] In addition, ammonia can inhibit nitric oxide (NO) synthase in endothelial cells by increasing the production of reactive oxygen species, reduce NO synthesis, and lead to decreased vasodilatory function, thereby affecting tissue perfusion.^[16] As revealed from a meta-analysis, ammonia is involved in the metabolism of multiple organs (e.g., liver, brain, kidney, muscle, and gastrointestinal tract), and hyperglycemia is recognized as an important clue to multiorgan dysfunction.^[17] Accordingly, ammonia can be considered a vital facilitator of the pathophysiological process of septic shock, thereby affecting the function of multiple organs by exerting an effect on the inflammatory response and tissue perfusion. The combination of ammonia and lactic acid helps overall assess the condition of septic shock.

Monitoring and treatment of hyperglycemia in critically ill patients

In clinical practice, blood ammonia monitoring is the first step of using blood ammonia to assess the disease. It is necessary to pay close attention to the variations of serum ammonia in patients clinically judged to be at high risk of serum ammonia (e.g., chronic basic liver disease, severe heart events, septic shock, gastrointestinal injury, or the application of specific drugs). At present, the detection of blood ammonia artery blood is considered to be more stable and reliable than venous blood. Furthermore, a range of interference factors should be avoided in the detection of blood ammonia (e.g., reducing the effect of muscle contractions). Blood samples should be collected simultaneously per day, and the samples should be sent to be tested in time after being collected, as an attempt to avoid the higher detection result attributed to the release of ammonia from red blood cells or the lower detection result due to the volatilization of ammonia from plasma.^{[18],[19],[20]}

High blood ammonia is associated with the occurrence, development, and mortality of severe diseases. Thus, timely intervention is of critical importance for clinical practice. In his systematic review of hyperglycemia, Haberle J emphasized the importance of the assessment and treatment of hyperglycemia; he considered that the treatment of hyperglycemia should be started immediately after the assessment of hyperglycemia without waiting for specific diagnosis because any delay in the treatment timing of the identification of hyperglycemia could cause patients to worsen.^[21] Patients with high blood ammonia should be given individualized and active treatment measures by complying with the blood ammonia level. The Middle East High blood ammonia and urea cycle disorders Academic group recommended that under conditions of blood ammonia higher than the normal upper limit, protein restriction and energy supplementation should be prioritized. With blood ammonia level of 250–500 mol/L, a preparation was made for blood purification treatment, while ammonia-lowering drugs were administrated. On the basis of the mentioned treatment, blood purification treatment was administered at 500 mol/L blood ammonia.^[21]

This study is considered the first provincial-level survey of the epidemiology of NHH in ICUs in China. The results of the present study indicate the real situation of NHH in Heilongjiang province on the whole, help formulate standardized diagnostic and treatment guidelines, and facilitate the individualized optimization of NHH treatment in ICU. The study is expected to be referenced for clinical practice of NHH management in China. Furthermore, the data will inspire subsequent research in other regions and nations.

Conclusion

This study is expected to provide a theoretical basis for the development of more scientific and standardized NHH diagnosis and treatment methods.

Study status

The preliminary work has been completed. Moreover, the data collection for this cross-sectional survey is to be conducted in 2020.

Financial support and sponsorship

This study was financially supported by the Scientific Research Project of Heilongjiang Health and Family Planning Commission (grant no. 2019045).

Conflicts of interest

There are no conflicts of interest.

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