prognostic values of Blood ammonia and partial pressure of ammonia on hospital arrival in

out-of-hospital cardiac arrests^{?,??,???,?,??}

Chih-Hao Lin MD ^a,?, Chih-Hsien Chi MD, PhD ^a, Shyu-Yu Wu MS ^b,

Hsiang-Chin Hsu MD ^a, Ying-Hsin Chang MD ^a, Yao-Yi Huang MD ^a, Chih-Jan Chang MD ^a,

Ming-Yuan Hong MD ^a, Tsung-Yu Chan MD ^a, Hsin-I Shih MD ^a

^aDepartment of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine,

National Cheng Kung University, Tainan 70403, Taiwan

^bDepartment of Electrical Engineering, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan

Received 4 March 2012; revised 4 April 2012; accepted 28 April 2012

Abstract

Purposes: outcome prediction for out-of-hospital cardiac arrest (OHCA) is of medical, ethical, and socioeconomic importance. We hypothesized that blood ammonia may reflect tissue hypoxia in OHCA patients and conducted this study to evaluate the prognostic value of ammonia for the return of spontaneous circulation (ROSC).

Methods: This prospective, observational study was conducted in a Tertiary university hospital between January 2008 and December 2008. The subjects consisted of OHCA patients who were sent to the emergency department (ED). The primary outcome was ROSC. The prognostic values were calculated for ammonia levels and the partial pressure of ammonia (pNH₃), and the results were depicted as a receiver operating characteristics curve with an area under the curve.

Results: Among 119 patients enrolled in this study, 28 patients (23.5%) achieved ROSC. Ammonia levels and pNH₃ in the non-ROSC group were significantly higher than those in the ROSC group (167.0 umol/L vs 80.0 umol/L, P b .05; 2.61 x 10^{- 5} vs 1.67 x 10^{- 5} mm Hg, P b .05, respectively). The Predictive capacity of area under the curve for ammonia and pNH₃ for non-ROSC was 0.85 (95% confidence interval, 0.75-0.95) and 0.73 (95% confidence interval, 0.61-0.84), respectively. The multivariate analysis confirmed that ammonia and pNH₃ are independent predictors of non-ROSC. The prognostic value of ammonia was better than that of pNH₃. The cutoff level for ammonia of 84 umol/L was 94.5% sensitive and 75.0% specific for predicting non-ROSC with a diagnostic accuracy of 89.9%.

^? Disclosures of conftict of interest: The authors disclose no confticts.

^?? Ethical adherence: The study procedures were in accordance with the ethical standards and were approved by the institutional review board in the

hospital.

^??? Funding and support: No financial support was granted.

^? Writing assistance: None.

^?? Author contributions: CHL conceived and supervised the study. All authors were involved in acquisition of data. CHL and SYW interpreted the data

and performed statistical analysis. CHL drafted the manuscript, and all authors contributed substantially to its revision. CHL and CHC offered administrative and

technical supports. CHL is the corresponding author who takes responsibility for the manuscript as a whole.

* Corresponding author. Tel.: + 886 6 2353535×2237, + 886 932989778; fax: + 886 6 2359562.

E-mail addresses: [email protected] (C.-H. Lin).

0735-6757/$ - see front matter (C) 2013 http://dx.doi.org/10.1016/j.ajem.2012.04.037

Conclusions: Hyperammonemia on ED arrival is independently predictive of non-ROSC for OHCA patients. The findings may offer useful information for clinical management.

(C) 2013

Introduction

Outcome prediction for out-of-hospital cardiac arrest (OHCA) is of medical, ethical, and socioeconomic impor- tance. The early management of OHCA is complicated by the lack of readily available prognostic predictors of the possible spontaneous return of circulation (ROSC). Higher survival rates have been observed in patients with witnessed ventricular tachycardia/ventricular fibrillation, bystander cardiopulmonary resuscitation (CPR), and Early defibrillation [1-4]. Several assessment tools or biomarkers, including Glasgow Coma Score [5], brain stem reftex [6], somatosensory-evoked potentials [7], end-tidal carbon dioxide [8,9], S-100 protein [10], neuron-specific enolase [11], Serum glucose [12], serum lactate [13], and brain natriuretic peptide [14], have been used to evaluate the outcome of cardiac arrest after ROSC. However, no single biomarker has been identified to reliably predict whether the cardiac arrest patient can or cannot achieve ROSC.

Hepatic dysfunction is a common finding in critically ill patients and is associated with longer Intensive care unit stays and increased hospital mortality [15]. Hypoxic hepatitis, also known as ischemic hepatitis or shock liver, is caused by the insufficient uptake of oxygen by the hepatocytes. Hypoxic Hepatitis Causes several complica- tions, such as spontaneous hypoglycemia, Respiratory insufficiency, and hyperammonemia. Blood ammonia is predictive of mortality for hospitalized patients with acute hepatic failure and can be used for risk stratification [16,17]. Recent studies have also suggested that blood ammonia levels at hospital arrival predict the neurologic outcome of patients with OHCA after ROSC [18]. We hypothesized that blood ammonia levels may reftect tissue hypoxia and that blood ammonia levels can thus be used to predict the likelihood of ROSC achievement for OHCA patients.

Ammonium (NH⁺), also known as ammonium ion, is an ionized form of ammonia (NH₃). Ammonia exists predom- inantly as ammonium in the blood, whereas a small pH- dependent fraction exists in a nonionized form (b 2%). The nonionized form of ammonia, reftected by the partial pressure of ammonia (pNH₃) [19], permeates cell mem- branes and is more toxic than the ionized form of ammonia. Because acidemia is one of the causes of cardiac arrests [20] and a decrease in pH may inftuence the value of pNH3, pNH3 should also be considered a Predictive tool for ROSC. Blood ammonia and blood gas analysis are diagnostic tests that are available in most emergency department (ED) settings. We conducted this study to evaluate the relationship

4

between ROSC and blood ammonia as well as pNH3 in OHCA patients.

Materials and methods

Study setting

This prospective, observational study was conducted in the ED of a tertiary university hospital in Taiwan between January 2008 and December 2008. The subjects of the study consisted of consecutive OHCA patients sent to the ED. Patients with a known pregnancy, severe hypothermia (defined as a body temperature b 30?C), a valid do-not- attempt-resuscitation order, or obvious signs of irreversible death and patients who were younger than 18 years old were excluded from the study. The signs of irreversible death included decapitation, hemicorporectomy, dependent lividi- ty, Rigor mortis, decomposition, and thermal carbonization without detectable vital signs. There were no rules concerning the termination of resuscitation in prehospital settings in Taiwan at the time of our study. All patients with witnessed and unwitnessed cardiac arrests assessed by emergency medical technicians were sent to hospitals unless obvious signs of irreversible death were present.

Demographic data were obtained from a prospective registry database. Basic and advanced life support measures were carried out by EMTs at the scene and/or emergency physicians in the ED according to standard protocols. The data comprise all of the information required for the international Utstein-style criteria [21,22], such as the patient’s history, cardiac risk factors, response intervals, initial cardiac rhythms, and the extent and amount of emergency care. The definitive cause of cardiac arrest was documented on discharge from the hospital or after the patient’s death in the hospital.

Emergency medical technicians may place intravenous lines, use advanced airway management devices, administer doses of epinephrine, and apply automated external defibrillators for OHCA patients before ED arrival. Basic and advanced cardiovascular life support was provided according to the 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emer- gency Cardiovascular Care [23] during the study period. Resuscitation was terminated if the patient exhibited persistent asystole after 30 minutes of advanced cardiovas- cular life support. All patients with sustained ROSC were admitted to the intensive care units and received standard intensive care treatment.

The study procedures were in accordance with the ethical standards and were approved by the institutional review board of the hospital.

Assessment of the blood ammonia levels and the pNH₃

Blood samples were collected from the femoral vessels of OHCA patients within 5 minutes after ED arrival. The blood sample of each patient was divided into several tubes or syringes for analysis.

The blood samples in tubes containing lithium heparin were cooled in ice-cold water before analysis and were transported to the clinical laboratory immediately. Ammonia levels were measured using Vitros NH₃ DT Slides with Vitros Fusion 5.1 FS Automated Chemistry Analyzer (Ortho Clinical Diagnostics, Johnson & Johnson Co., NJ). The Vitros NH₃ DT Slide is a multilayered, analytical element that is coated on a polyester support. Water and nonprotei- naceous components travel to the underlying buffered reagent layer, and the ammonium ions are converted to gaseous ammonia. The semipermeable membrane allows only ammonia to pass through, which prevents buffer or hydroxyl ions from reaching the indicator layer and thus avoids the inftuence of possible acidemia. The detection range for blood ammonia in the assay was 1 to 500 umol/L, and the institutional reference range was 9 to 33 umol/L. Blood ammonia levels of 500 umol/L were considered beyond the upper limits of detection.

The blood gas samples in Luer slip syringes containing heparin were analyzed to obtain the pH value. The blood gas analysis was determined using i-STAT EG7 + cartridges with i-STAT System (Abbott Point of Care Inc., NJ). The detection range for blood pH was 6.5 to 8.2. Combining the mass balance equation and Henry’s law [24], the partial pNH₃ can be calculated as follows: p[NH₃] = (K_H x [NH₃]_T)/(1 + [H⁺]/K_a), where [NH₃]_T = total blood ammonia, K_H for ammonia = 1.75 x 10^{- 3}, K_a = 9.8 x 10^{- 10}, and [H⁺] is derived from the pH values as the antilog (^-pH).

The patients who did not follow the aforementioned blood sampling procedures were excluded. Patients whose labora- tory results were not available were also excluded. The physicians who provided medical care during the study period had no knowledge of the study results. therapeutic decisions were not biased by assay measurements.

Outcome measures

The primary outcome was ROSC. Return of spontaneous circulation was defined as an organized electrocardiogram with a palpable pulse. Patients with the return of a palpable pulse for less than 5 minutes were considered to not have achieved ROSC.

Statistical analysis

Data were collected by the designated registered nurses and were entered into an Excel (Microsoft Corp, Redmond, WA) spreadsheet. The study physicians per- formed manual checks on the accuracy of data entry monthly for further analysis.

The skewness of data distribution was checked before the analysis. Categorical variables are shown as a number with a percentage, and quantitative data are shown as a median value with an interquartile range (IQR). The ROSC achievement group and the non-ROSC group were compared using the Mann-Whitney U test for continuous variables and the ?2 test or Fisher test for discrete variables, wherever applicable. The sensitivity and spec- ificity of the prediction of non-ROSC were calculated for different cutoff values of blood ammonia levels and the pNH₃, and the results were depicted as a receiver operating characteristics (ROC) curve with an area under the curve (AUC).

We carried out univariate analysis of the clinical and

biochemical variables that could inftuence ROSC. The variables available on ED admission were considered for inclusion in the logistic regression. The significant variables were dichotomized using discriminant values derived by constructing ROC curves for each variable. The odds ratio with a 95% confidence interval (95% CI) was calculated for each variable. The predicted probability of non-ROSC was derived from the variables found to be significant after logistic regression analysis.

Two-tailed P b .05 was considered significant. We used the SPSS software (version 17; SPSS Inc, Chicago, IL) for the statistical analysis.

Results

A total of 175 consecutive OHCA patients sent to the ED during the study period were evaluated for inclusion. Fifty- six patients were excluded because of an age of younger than 18 years (n = 4), obvious signs of irreversible death (n = 12), severe hypothermia (n = 2), valid do-not-attempt-resuscita- tion orders (n = 16), inconsistent blood sampling procedures (n = 14), or unavailable laboratory data (n = 8). A final total of 119 OHCA patients (60 men and 59 women) were included in this study. The median age of the included patients was 74.0 years.

Of the 119 patients, 28 patients (23.5%) achieved ROSC, and 91 (76.5%) did not. Table 1 compares the baseline characteristics between the 2 groups. The 10 clinical and biochemical variables that proved to be significantly different between the 2 groups are as follows: the etiology of cardiac arrest, initial cardiac rhythm, the presence of bystander CPR, ammonia, pNH₃, alanine aminotransferase (ALT), creatinine, potassium, pH, and PCO₂.

Total OHCA		Non-ROSC group	ROSC group	P
Total	119	91	28
Age (y)	74 (61.0-80.5)	74.0 (59.0-81.0)	73.5 (63.5-79.0)	.856
Sex (male)	60 (50.4%)	47 (51.6%)	13 (46.4%)	.927
Etiology (nontrauma)	94 (79.0%)	70 (76.9%)	24 (85.7%)	b.05
Witness cardiac arrest	49 (41.1%)	33 (36.3%)	16 (57.1%)	.054
Bystander CPR	10 (8.4%)	8 (8.79%)	2 (7.14%)	b.05
Initial cardiac rhythm	28 (23.5%)	18 (15.1%)	10 (35.7%)	b.05
(shockable)
Ammonia (umol/L)	150.0 (108.0-187.5)	167.0 (120.0-190.0)	80.0 (47.5-96.0)	b.05
pNH3 (10- 5 mm Hg)	2.38 (1.67-3.47)	2.61 (1.88-3.81)	1.67 (0.89-2.31)	b.05
White blood counts	10.7 (7.8-14.2)	10.5 (7.6-13.8)	11.7 (8.8-17.2)	.319
(10- 3/uL)
Hemoglobin level (g/dL)	11.3 (8.6-13.6)	11.2 (8.6-13.4)	11.5 (8.5-14.7)	.694
AST (U/L)	81 (42.5-208.0)	84 (44.0-270.5)	52 (34.5-111.0)	.06
ALT (U/L)	39 (19-131.5)	42 (21.5-151.0)	24 (15.0-63.0)	b.05
Creatinine (mg/dL)	1.7 (1.1-2.6)	1.6 (1.1-2.3)	2.4 (1.4-4.2)	b.05
Sodium (mmol/L)	141.0 (137.0-144.0)	142.0 (138.0-145.0)	140.5 (134.5-142.5)	.110
Potassium (mmol/L)	5.6 (4.6-7.3)	5.8 (4.6-7.5)	4.9 (4.3-6.2)	b.05
Glucose (mg/dL)	148.0 (89.5-211.5)	142.0 (82.0-212.0)	165.0 (118.0-202.0)	.497
pH	7.0 (6.9-7.2)	7.0 (6.8-7.2)	7.1 (7.0-7.2)	b.05
PO2 (mm Hg)	20.0 (13.0-38.7)	20.0 (12.0-37.0)	21.9 (14.5-71.0)	.145
PCO2 (mm Hg)	67.7(49.2-89.7)	71.6(55.0-100.0)	55.3(44.0-69.9)	b.05
Bicarbonate (mmol/L)	19.5 (12.7-23.9)	20 (13.1-24.3)	18.6 (12.4-21.5)	.34
BE (mmol/L)	- 10 (- 19.0 to - 6.0)	- 9.7 (- 19.5 to - 6.0)	- 12 (- 17 to - 5.6)	.86
Categorical variables were given as number (percentage), whereas quantitative data were given as median (interquartile range). P value comparing non-ROSC achievement group and ROSC achievement group less than .05 was considered significant. AST indicates aspartate aminotransferase; ALT, alanine aminotransferase; BE, base excess.

Ammonia levels and pNH₃ values at ED arrival

Table 1 Clinical and Biochemical parameters among patients with OHCA

The results of blood gas analysis and ammonia levels were obtained within 2 and 15 minutes after blood sampling, respectively. The median ammonia level for OHCA patients at ED arrival was 150 umol/L (IQR, 108-187.5 umol/L). The blood ammonia levels of 115 patients (96.6%) exceeded the upper institutional normal limit of 33 umol/L.

Ammonia levels and pNH₃ values in the non-ROSC group were significantly higher than the levels in the ROSC achievement group (P b .05), as shown in Fig. 1. The median ammonia level was 167 umol/L (IQR, 120-190 umol/L) in the non-ROSC group and 80 umol/L (IQR, 47.5-96.0 umol/L) in the ROSC achievement group. The median pNH₃ value was 2.61 x 10^{- 5} mm Hg (IQR, 1.88 x 10^{- 5}-3.81 x 10^{- 5} mm Hg) in the non-ROSC group and

1.67 x 10^{- 5} mm Hg (IQR, 0.89 x 10^{- 5}-2.31 x 10^{- 5} mm

Hg) in the ROSC achievement group.

The prognostic value of ammonia levels

An ROC curve was plotted with the ammonia levels of each patient as the independent variable and non-ROSC as the outcome variable, as shown in Fig. 2A. The AUC was

0.85 (95% CI, 0.75-0.95). The optimal cutoff level for ammonia was 84 umol/L and was found to be 94.5%

sensitive and 75.0% specific for predicting non-ROSC with a diagnostic accuracy of 89.9%. The pretest odds ratio was 3.2, and the posttest odds ratio was 12.3.

Prognostic value of pNH₃

The ROC curve for pNH₃ values and non-ROSC is shown in Fig. 2B, with an AUC of 0.73 (95% CI, 0.61-0.84). The optimal cutoff pNH₃ value of 1.89 x 10^{- 5} mm Hg was found to be 74.7% sensitive and 71.4% specific for predicting non- ROSC with a diagnostic accuracy of 73.9%. The posttest odds ratio was 8.5.

Comparison of the non-ROSC and the ROSC achievement group

The univariate analysis showed that 10 clinical and biochemical variables significantly inftuenced ROSC achievement. The results are shown in Table 1. These variables were analyzed using logistic regression analysis with non-ROSC as the dependent variable. These variables were dichotomized for best discrimination between the non- ROSC and ROSC achievement groups using the cutoff values derived from the construction of individual ROC curves, as shown in Table 2. The following 5 variables were found to be independent predictors of non-ROSC: blood ammonia,

Fig. 1 Comparison of blood ammonia levels (A) and the partial pressures of ammonia (B) of the non-ROSC group and the ROSC group.

pNH₃, ALT, potassium, and PCO₂. The remaining variables, which include the etiology of the cardiac arrest, the presence of bystander CPR, the initial cardiac rhythm, Creatinine levels, and pH values, either had no effect or lost their independent predictive capacity in the multivariate model.

The blood ammonia level, with an assigned cutoff value of 84 umol/L, had a much higher odds ratio (51.6; 95% CI, 14.9-178.8) compared with the other variables.

Comparative prognostic value of ammonia levels and pNH₃

The prognostic value of blood ammonia and pNH₃ at ED arrival was analyzed in the 119 OHCA patients. The findings from the ROC curves constructed with non-ROSC as the outcome variable showed that the AUC was greater for ammonia levels than for pNH₃ values (0.85 vs 0.73). The

Fig. 2 A ROC curve with an AUC for non-ROSC was depicted for blood ammonia levels (A) and the partial pressure of ammonia (B).

Non-ROSC group (n = 91)		ROSC group (n = 28)	P	Odds ratio (95% CI)
Etiology			.32	3.2 (1.0-10.3)
Nontrauma	70 (76.9%)	24 (85.7%)
Trauma	21 (23.1%)	4 (14.3%)
Bystander CPR			.78	1.3 (0.3-6.3)
Absent	83 (91.2%)	26 (92.6%)
Present	8 (8.8%)	2 (7.4%)
Initial cardiac rhythm			.08	0.4 (0.2-1.1)
Nonshockable	73 (80.2%)	18 (64.3%)
Shockable	18 (19.8%)	10 (35.7%)
Ammonia (umol/L)			b.05	51.6 (14.9-178.8)
b 84.0	5 (5.5%)	21 (75.0%)
>= 84.0	86 (94.5%)	7 (25.0%)
pNH3 (10- 5 mm Hg)			b.05	7.4 (2.9-19.0)
b 1.89	23 (25.3%)	20 (71.4%)
>= 1.89	68 (74.7%)	8 (28.6%)
ALT (U/L)			b.05	3.1 (1.3-7.6)
b 36.5	37 (40.7%)	19 (67.9%)
>= 36.5	54 (59.3%)	9 (32.1%)
Creatinine (mg/dL)			.61	1.4 (0.3-6.0)
b 0.85	7 (7.7%)	3 (10.7%)
>= 0.85	84 (92.3%)	25 (89.3%)
Potassium (mmol/L)			b.05	2.9 (1.2-7.2)
b 5.5	38 (42.8%)	19 (67.9%)
>= 5.5	53 (58.2%)	9 (32.1%)
pH			.33	N/A
b 7.36	88 (96.7%)	28 (100%)
>= 7.36	3 (3.3%)	0 (0%)
PCO2 (mm Hg)			b.05	11.6 (2.6-52.0)
b 78.4	48 (52.7%)	26 (92.9%)
>= 78.4	43 (47.3%)	2 (7.1%)
Odds ratio with 95% CI for each variable was listed. N/A indicates not applicable.

diagnostic accuracy and posttest odds ratio of ammonia levels for non-ROSC were also better than those of pNH₃ (89.9% vs 73.9% and 12.3 vs 8.5, respectively). The multivariate analysis confirmed that the odds ratio of ammonia for non-ROSC was much higher than that of pNH₃ (51.6 vs 7.4), as shown in Table 2.

Table 2 Clinical and biochemical variables significantly inftuencing achievement of ROSC were dichotomized using discriminant values derived by constructing ROC curves for each variable

Discussion

We found that the ammonia levels at ED arrival were significantly higher among non-ROSC patients than among ROSC patients. The optimal cutoff level for ammonia that was predictive for non-ROSC in this study was 84 umol/L. Our findings are consistent with the results of previous studies. Nagamine [25] found that a blood ammonia level of less than 180 ug/dL (105.6 umol/L) was predictive for full Neurologic recovery in witnessed OHCA patients. Yanagawa et al [26] showed that ammonia levels were significantly higher among the survivors with higher Cerebral Performance Category scores 1 month after cardiac arrest than among survivors with lower CPC scores (327 vs 124 ug/dL,

P = .001). Shinozaki et al [18] also reported that a blood ammonia level above 170 ug/dL (99.8 umol/L) was independently predictive of higher CPC scores 6 months of cardiac arrest.

The pKbh of ammonia, which is approximately 8.90 at 37 ?C [24], is close to the normal blood pH of 7.4. Any change in blood pH would significantly affect the ratio of nonionized to ionized ammonia. A greater percentage of ammonia may enter the brain as the blood pH rises because of an increase in the amount of ammonia present in its nonionized form. Bhatia et al [17] demonstrated that an arterial ammonia level greater than over equal to 124 umol/ L had a diagnostic accuracy of 77.5% for predicting mortality in patients with acute hepatic failure. However, their study showed no significant difference in prognostic values between the total blood ammonia level and pNH₃. In our study, we found that the blood ammonia level was superior to pNH₃ for predicting non-ROSC among OHCA patients. The blood ammonia level alone may then suffice for predictive purposes.

Hyperammonemia may result from an increased pro- duction of ammonia. In mammals, skeletal muscle and

Intestinal mucosa are major contributors to ammonia production [27]. Protein is broken down, and glutamate is transaminated to form glutamine in the skeletal muscles. Glutamine is the temporary storage form of waste nitrogen and is a major source of ammonia if deaminated by glutaminase. In the intestinal mucosa, ammonia is produced after the uptake of amino acids because of glutamine deamination. 5?-adenosine monophosphate deaminase, which can destroy adenosine [28,29] and cause systolic arrest or arrhythmia [30], generates ammonia from adenosine monophosphate during muscle contraction and rigor mortis [31]. Nagamine [25] found that the blood ammonia level of OHCA patients at hospital arrival was positively correlated with the time elapsed from confirma- tion of cardiac arrest to hospital arrival. Previous studies have also shown a strong correlation between the processes of blood lactate and ammonia production in anaerobic exercise [32,33]. Ishida et al [34] reported that the development of respiratory and metabolic acidosis during cardiac arrest may induce the release of ammonia from red blood cells. Because of these findings, we hypothesize that hyperammonemia may result from an increase in the production of ammonia when the tissues are in a state of oxygen depletion due to cardiac arrest. The amount of ammonia production may correlate with the time elapsed from cardiac arrest. The blood ammonia level can then be predictive of non-ROSC of OHCA patients.

Hyperammonemia may also result from a decrease in

the elimination of ammonia. The liver and kidney are responsible for the detoxification of portal ammonia and the export of ammonia. In the kidney, ammonia is formed from glutamine deamination. However, renal ammonia production mainly contributes to the buffering of H+ ions, whereas the excretion of ammonia in urine plays only a minor role in the overall ammonia detoxification [27]. The liver plays a vital role in the detoxification of ammonia because the Urea cycle located in periportal hepatocytes detoxifies a vast amount of surplus nitrogen [35]. Pneumatosis intestinalis and hepatic portal venous gas, which most commonly occur second- ary to intestinal ischemia and necrosis, have been observed in patients after CPR [36,37] and are associated with grave outcomes [38]. The poor mesenteric and portal perfusion in patients during cardiac arrest even with CPR may cause hypoxic hepatocytic necrosis and thus impair ammonia elimination. Pneumatosis intestinalis may affect the intestinal microorganisms with enzymes, which may enable protein and urea degradation and lead to hyperammonemia [39].

The pathogenesis of hyperammonemia may include impaired bioenergetics, altered neurotransmission, gluta- mate-mediated excitotoxicity, electrophysiologic derange- ments, oxidative and nitrosative stress, and mitochondrial dysfunction [40-43]. Ammonia is mainly toxic to the brain, and most of the complications associated with hyperammo- nemia are neurologic. Hypothermia has been reported to

decrease cerebral edema and improve encephalopathy in patients with acute hepatic failure through reducing cerebral uptake of ammonia [40]. Hyperammonemia was also reported to be predictive of Poor neurologic outcomes in nontraumatic OHCA patients [18,25].

We found that hyperammonemia was independently predictive of non-ROSC in OHCA patients. The findings of this study may offer useful information on the clinical management of OHCA patients. Physicians should consider terminating resuscitation efforts for OHCA patients if the initial ammonia levels are extremely high. Further studies are also needed to clarify the pathophysiologic significance of ammonia and the mechanism of hyperammonemia in patients with cardiac arrest.

Limitations

The blood samples were collected from the femoral vessels of OHCA patients on ED arrival. However, we could not be sure whether the blood was arterial or venous due to the technical difficulties of blood sampling during resusci- tation. To our knowledge, the difference in the ammonia levels of arterial and venous blood during resuscitation has not been determined.

The blood samples in this study were obtained from patients within 5 minutes after ED arrival. We did not analyze the correlation of the blood ammonia level with the time elapsed from confirmation of cardiac arrest to ED arrival. Our study included both witnessed and unwitnessed cardiac arrest patients, and thus, the time between arrest and laboratory sampling was unknown in some patients.

An awareness of the laboratory reports of biomarkers in this study was not blinded. However, therapeutic decisions were not biased because the physicians in charge of OHCA patients could not know the optical cutoff values until the study was completed. The results of ammonia levels were obtained within 15 minutes in this study. Using ammonia levels to predict ROSC would be more feasible and practical if the results were obtained sooner.

Conclusions

A blood ammonia level on ED arrival greater than 84 umol/L was 94.5% sensitive and 75.0% specific for predicting non-ROSC in OHCA patients with a diagnostic accuracy of 89.9%. The predictive value of the blood ammonia level for non-ROSC is better than that of the pNH₃.

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