This prospective, multicenter study reveals prognostic biomarkers of NHH for critically ill patients who were hospitalized at ICUs, in which 1,060 patients from 11 ICUs were recruited. Our findings indicated that patients with poor prognosis had higher levels of M-Ammonia, and serum lactic acid, ammonia, TBil and APACHE-II scores on admission to ICU were independent predictors of prognosis. Moreover, the SOFA score was common risk factors for ICU patients with poor prognosis.
Increased blood lactic acid and ammonia levels are byproducts of ATP production and associated with higher levels of anaerobic metabolic activity.(24) Critically ill patients are at a higher risk of hyperammonemia because of increased ammonia generation and decreased blood ammonia clearance. Infection by bacteria which rely on urease to hydrolyze urea to carbon dioxide and ammonia, as well as pneumonia, fever, and other stressors may ultimately result in NHH.(25) Further, gastrointestinal bleeding or steroid hormone-induced damages to the gastrointestinal tract can lead to increased protein breakdown and promote ammonia generation.(26) Moreover, several factors may hinder blood ammonia clearance: (1) acute/chronic liver failure caused by drugs or toxins, infections, and autoimmune diseases, leading to diminished ammonia clearance by the liver; (2) salicylic acid, valproic acid, and other drugs may diminish the mitochondrial function of liver cells and inhibit the activity of rate-limiting enzymes in the urea cycle, causing urea cycle disorders and subsequently increased blood ammonia level; (3) uremia caused by a decreased renal blood flow, glomerular filtration rate, and renal handling of urea in acute kidney injury may result in an increased blood ammonia level.(27) Therefore, a higher blood ammonia level can indicate both loss of hepatic ammonia clearance and a state of disordered energy metabolism.
Changes in energy metabolism are prevalent in critically ill patients admitted to ICU and can lead to a significant increase in blood ammonia levels.(28) However, to date, only a limited number of studies have reported the incidence of NHH. Nonetheless, a prospective study conducted by Prado et al. indicated that the incidence of NHH in patients with severe diseases was as high as 73%, and blood ammonia levels were significantly correlated with the rate of mortality. Our previous research confirmed that an increased serum ammonia level is not only commonly observed in ICU patients, but also is correlated to the disease severity and patient prognosis.(29) However, it is easy to overlook NHH as hyperammonemia is not related to liver disease in these patients. To date, no multicenter, prospective study on NHH patients admitted to ICU has been conducted. Thus, the current research was carried out to eliminate the mentioned clinical gap.
Patients with congestive heart failure often have high blood ammonia levels associated with reduced cardiac function. Recently, Bing et al. hypothesized that treating elevated circulating ammonia levels may prevent and reverse heart failure.(16) Elevated cardiac loads change the metabolic balance and lead to an ammonia surplus eventually causing myocardial cell apoptosis. A therapeutic strategy targeting hyperammonemia can prevent adverse cardiac events in early stages and reverse heart failure in later stages.(13)
It is noteworthy that ammonia is involved in the functional metabolism in multiple organs, such as liver, brain, kidney, muscles, and gastrointestinal tract. Therefore, hyperammonemia can indicate multiple organ dysfunction. It may also be involved in in the pathogenesis of septic shock via inflammatory responses and impaired tissue perfusion.(30, 31) In the present research, we examined whether there could be differences in the different prognosis between distinct types of diseases (e.g., Sepsis, Kidney failure), and no significant differences were identified, consistent with previously reported results in severity of hyperammonemia.(17) This may be attributed to the diverse and complicated etiology of NHH, which indicating the prognosis. Overall energy expenditure and severity of disease are the key factors contributing to the occurrence of NHH.
Our findings demonstrated that patients with poor prognoses had higher levels of average serum ammonia as well as a higher incidence of severe diseases (a higher APACHE-II score) and organ dysfunction (an increased SOFA score), lower level of consciousness, longer period of hospitalization, and higher costs associated with the length of stay at ICU compared with cases with a favorable prognosis. Our previous single-center study revealed that severe NHH patients (serum ammonia level ≥ 100 µmol/L) required specialized treatments(29). As for the prognosis of patients, the logistic regression and ROC curve analyses demonstrated the competitive power of disease severity (the APACHE-II score) or serum ammonia in predicting a poor prognosis of severe NHH patients. Due to the extremely fast clearance of blood ammonia in the body, about 7.7 h, an occasional increase in the blood ammonia level can only reflect a transient high metabolic state in the body.(32, 33) M-ammonia is defined as continuously increased blood ammonia level, and is accompanied by a high mortality rate, demonstrating that solicitous and continuous monitoring of serum ammonia level is valuable in the prediction of the prognosis of ICU patients.
The serum ammonia level has widely been used as a biomarker for the diagnosis and treatment of liver failure, and for identification of hepatic associated with hyperammonemia.(34) Treating high serum ammonia levels effectively restores consciousness, attenuates the incidence of cerebral edema, and improves overall morbidity and mortality. However, the clinical significance of NHH as a prognostic indicator has long been neglected. The present study reveals that an elevated serum ammonia level is indicator of disease severity and prognosis in patients without liver diseases. At present, the majority of commonly used ammonia-lowering drugs are targeted at hyperglycemia-related hyperammonemia and hepatic encephalopathy caused by liver diseases.(35, 36) Thus, further research is warranted to indicate whether they improve outcomes in NHH patients.
Several limitations in the present study must be acknowledged. First, as our study enrolled heterogenous patients with normal or hyperammonemia, the causal relationship between non-hepatic hyperammonemia and poor outcome cannot be fully determined based on the present study. As we recruited patients from more than 10 centers, inter-center consistency needs to be considered. Expectedly, although NHH is a common metabolic disorder in daily ICU practice, its incidence varies among different medical centers. This may be explained by the differences in the number of participants, detection instruments and protocols, and prevalence of underlying diseases. Furthermore, since hyperammonemia was frequent in patients who died in the hospital, it is possible that early death (before ammonia measurement) could have led to further underreporting.