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Gastric regurgitation predicts neurological outcome in out-of-hospital cardiac arrest survivors

Published:August 22, 2020DOI:https://doi.org/10.1016/j.ejim.2020.08.010

      Highlights

      • Gastric regurgitation during the first day of hospital admission is an early, easily available and independent predictor for poor neurological outcome in comatose out-of-hospital cardiac arrest survivors.
      • Association between gastric regurgitation and poor neurological outcome is more pronounced in multivariable models containing the clinical confounders first rhythm non-shockable, private location of collapse and cardiac arrest unwitnessed.
      • Measurement of gastric regurgitation is simple, inexpensive and routinely performed in critical care units.

      Abstract

      Hypoxic-ischemic brain injury can affect and disturb the autonomous nervous system (ANS), which regulates various visceral systems including the gastro-intestinal and emetic system. The present study aimed to analyze the predictive value of gastric regurgitation (GReg) for neurological outcome in out-of-hospital cardiac arrest (OHCA) survivors. In this prospective, single-center study, 79 OHCA survivors treated at a university-affiliated tertiary care centre were included and GReg was measured at the first day after successful cardiopulmonary resuscitation. Neurological outcome was assessed by the Cerebral Performance Categories score at discharge. Seventy-six percent of the study population had a poor neurological outcome. GReg was found to be associated with poor neurological outcome with an adjusted OR of 5.37 (95% CI 1.41–20.46; p = 0.01). The area under the ROC curve for GReg was 0.69 (95% CI, 0.56–0.81) for poor neurological outcome. GReg on the first day after OHCA is an early, strong and independent predictor for poor neurological outcome in comatose OHCA survivors. These results are particularly compelling because measurement of GReg is inexpensive and routinely performed in critical care units.

      Keywords

      1. Introduction

      Neurological prognostication after out-of-hospital cardiac arrest (OHCA) is challenging due to the lack of early and reliable predictors for clinically relevant brain damage [
      • Rossetti A.O.
      • Rabinstein A.A.
      • Oddo M.
      Neurological prognostication of outcome in patients in coma after cardiac arrest.
      ]. The identification of reliable neurological outcome predictors would essentially guide caregivers in their decision-making process for evaluating further therapeutic strategies and support physicians and families in fateful medical decisions.
      Hypoxic-ischemic brain injury can affect and disturb the autonomous nervous system (ANS) [
      • Lee R.H.
      • Couto E.S.A.
      • Lerner F.M.
      • Wilkins C.S.
      • Valido S.E.
      • Klein D.D.
      • et al.
      Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.
      ,
      • De Raedt S.
      • De Vos A.
      • De Keyser J.
      Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area?.
      ,
      • McLaren A.
      • Kerr S.
      • Allan L.
      • Steen I.N.
      • Ballard C.
      • Allen J.
      • et al.
      Autonomic function is impaired in elderly stroke survivors.
      ]. This ANS regulates various cardiovascular and visceral functions including the gastro-intestinal and emetic system. Dysfunction of the ANS was found to be associated with changes in heart rate variability as well as with disturbances of gastric and intestinal motor functions [
      • Pirtniecks A.
      • Smith L.F.
      • Thorpe J.A.
      Autonomic dysfunction in non-specific disorders of oesophageal motility.
      ,
      • Tahsili-Fahadan P.
      • Geocadin RG.
      Heart-brain axis: effects of neurologic injury on cardiovascular function.
      ]. Analyses of heart rate variability have recently been found useful for neurological outcome in OHCA patients [
      • Endoh H.
      • Kamimura N.
      • Honda H.
      • Nitta M.
      Early prognostication of neurological outcome by heart rate variability in adult patients with out-of-hospital sudden cardiac arrest.
      ]. The predictive value of gastric and intestinal motor functions has not been analyzed yet.
      We hypothesized that the amount of gastric regurgitation (GReg) could be a novel, inexpensive, simple determinable and early prognostic marker for prediction of brain injury and neurological outcome in OHCA survivors. Therefore, we analyzed for the first time the prognostic significance of GReg volume on the first day of hospital admission on neurological outcome in OHCA survivors.

      2. Material and methods

      2.1 Study design and patients

      The present investigation is a substudy of a prospective, observational, single-center trial performed between October 2013 and May 2016 [
      • Distelmaier K.
      • Muqaku B.
      • Wurm R.
      • Arfsten H.
      • Seidel S.
      • Kovacs G.G.
      • et al.
      Proteomics-enriched prediction model for poor neurologic outcome in cardiac arrest survivors.
      ]. We recruited unconscious patients after OHCA on arrival at the emergency department and observed them till discharge from intensive care unit (ICU) of the Medical University of Vienna as previously described [
      • Distelmaier K.
      • Muqaku B.
      • Wurm R.
      • Arfsten H.
      • Seidel S.
      • Kovacs G.G.
      • et al.
      Proteomics-enriched prediction model for poor neurologic outcome in cardiac arrest survivors.
      ]. The study protocol was approved by the Ethics Committee of the Medical University of Vienna (EK 1740/2013) and is in accordance with the Declaration of Helsinki. This study is registered with ClinicalTrials.gov, number NCT01960699.

      2.2 Measures and procedures

      All OHCA patients were treated during cardiopulmonary resuscitation (CPR) and in post-resuscitation management according to current guidelines [
      • Callaway C.W.
      • Soar J.
      • Aibiki M.
      • Bottiger B.W.
      • Brooks S.C.
      • Deakin C.D.
      • et al.
      Part 4: advanced life support: 2015 international consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      ]. All patients were routinely treated with targeted temperature management at 33°C to 36°C for 24 h. Cardiac arrest data sets of each individual patient were recorded in “Utstein” Style [
      • Jacobs I.
      • Nadkarni V.
      • Bahr J.
      • Berg R.A.
      • Billi J.E.
      • Bossaert L.
      • et al.
      Cardiac arrest and cardiopulmonary resuscitation outcome reports: update and simplification of the Utstein templates for resuscitation registries: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian Resuscitation Council, New Zealand Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Councils of Southern Africa).
      ]. Neurological outcome was assessed at ICU discharge by experienced neurologists using Cerebral Performance Categories (CPC) score [
      • Jennett B.
      • Bond M.
      Assessment of outcome after severe brain damage.
      ] and dichotomized into favorable neurological outcome (CPC ≤2) and poor neurological outcome (CPC score ≥ 3). A nasogastric tube was routinely placed in the stomach of the patients at hospital admission. GReg was recorded during the first full day of hospital admission. Therefore, clinical caregivers measured the cumulative volume of the draining contents through the nasogastric tube every two hours. Volumes of the first full day of hospital admission of each patient were accumulated and defined as GReg of first day. Definite cause of OHCA was determined by the treating physicians during the hospital stay.

      2.3 Statistical analysis

      Discrete data were presented as count and percentage and analyzed by using chi-square test. Continuous data were presented as median and interquartile range (IQR) and compared by using Mann–Whitney statistics. Binary logistic regression analyses were applied to assess the association between GReg during the first day of hospital admission and poor neurological outcome. Therefore, the study population was stratified into patients with and without GReg. Binary logistic regression analyses were applied to assess the association of GReg during the first day of hospital admission and other clinical factors with poor neurological outcome by univariate and multivariable models. [
      • Aschauer S.
      • Dorffner G.
      • Sterz F.
      • Erdogmus A.
      • Laggner A.
      A prediction tool for initial out-of-hospital cardiac arrest survivors.
      ]. The predictors of the multivariable model were selected by computing receiver-operating characteristic (ROC) analyses, whereby a cut-off of an area under the ROC of > 0.60 was chosen. Two-sided p values of less than 0.05 were used to indicate statistical significance. SPSS, version 25.0 (IBM Corp) was used for all analyses.

      3. Results

      3.1 Baseline characteristics

      A total of 100 OHCA patients were enrolled in the present study. Twenty-one patients were excluded as GReg was not recorded on the first day of hospital admission. Finally, the presence of GReg was assessed in 79 comatose and intubated patients on the first day of hospital admission. A Consolidated Statement of Reporting Trials flow diagram of the study population is depicted in Fig. 1. Seventy-six percent of the study population had a poor neurological outcome at ICU discharge. The underlying cause of OHCA was of cardiac origin in 86%. Coronary angiography was performed in 62% of OHCA patients and coronary revascularization was done in 51%. GReg was observed in forty patients (51%) with a median amount of 225 ml (IQR 100–400ml) on the first day of hospital admission. No patient received enteral nutrition during that time period. Detailed baseline characteristics of the total study population and stratified into patients with and without GReg are displayed in Table 1.
      Fig 1
      Fig. 1Consort flow diagram of the study population. OHCA: Out-of-hospital cardiac arrest, ROSC: Return of spontaneous circulation.
      Table 1Baseline characteristic of study population and stratification regarding gastric regurgitation on first day of hospital admission.
      Total study population (n = 79)no GReg at first day (n = 39)GReg at first day (n = 40)p-value
      Gastro-esophageal reflux at first day, ml median (IQR)20 (0–250)0 (0–0)225 (100–400)
      Age, yr, median (IQR)60 (51–70)60 (51–71)58 (48–69)0.536
      Female sex, n (%)16 (20.3)11 (28.2)5 (12.5)0.082
      Cardiac arrest witnessed, n (%)63 (79.7)32 (82.1)31 (77.5)0.615
      Location of collapse0.737
        Private, n (%)39 (49.4)20 (51.3)19 (47.5)
        Public, n (%)40 (50.6)19 (48.7)21 (52.5)
      Definite cause of cardiac arrest0.924
        Cardiac, n (%)68 (86.1)33 (84.6)35 (87.5)
        Pulmonary, n (%)9 (11.4)5 (12.8)4 (10.0)
        Unknown, n (%)2 (2.5)1 (2.6)1 (2.5)
      First monitored rhythm0.470
        Shockable rhythm
          Ventricular fibrillation, n (%)55 (69.6)25 (64.1)30 (75.0)
          Ventricular tachycardia, n (%)1 (1.3)1 (2.6)0 (0.0)
        Asystole, n (%)9 (11.4)5 (12.8)4 (10.0)
        Pulseless electrical activity, n (%)12 (15.2)6 (15.4)6 (15.0)
        Unknown first rhythm, n (%)2 (2.5)2 (5.1)0 (0.0)
      Time from cardiac arrest to event - in minutes
        Start of life support after collapse, min, median (min-max)0 (0–8)0 (0–1)0 (0–8)0.123
        Alarm till arrival of ambulance, min, median (IQR)6 (5–8)6 (4–8)7 (5–9)0.170
        Return of spontaneous circulation, min, median (IQR)30 (16–45)26 (13–41)33 (18–47)0.251
        First administration of epinephrine, min, median (IQR)13 (9–15)13 (3–15)13 (10–15)0.587
        Dose of epinephrine administered, mg, median (IQR)4 (2–5)3(1–5)4 (3–6)0.194
      Mode of cooling0.144
        Invasive, n (%)59 (74.7)28 (71.8)31 (77.5)
        Non-invasive, n (%)10 (12.7)8 (20.5)2 (5.0)
        Combined, n (%)6 (7.6)2 (5.1)4 (10.0)
        Unknown, n (%)4 (5.1)1 (2.6)3 (7.5)
      Medical history
        Hypertension, n (%)33 (41.8)17 (43.6)16 (40.0)0.746
        History of smoking, n (%)29 (36.7)10 (25.6)19 (47.5)0.044
        Diabetes, n (%)15 (19.0)6 (15.4)9 (22.5)0.449
        Acute myocardial infarction, n (%)15 (19.0)6 (15.4)9 (22.5)0.420
        Coronary artery disease, n (%)18 (22.8)7 (17.9)11 (27.5)0.312
        Chronic heart failure, n (%)11 (13.9)4 (10.3)7 (17.5)0.352
        COPD, n (%)8 (10.1)1 (2.6)7 (17.5)0.028
      Treatment on day 1
        Proton-pump inhibitor, n (%)79 (100.0)39 (100.0)40 (100.0)1.000
        Metoclopramide, n (%)7 (8.9)4 (10.3)3 (8.1)0.691
        Erythromycin, n (%)0 (0.0)0 (0.0)0 (0.0)1.000
        Enteral nutrition ml, median (IQR)0 (0–129)0 (0–89)0 (0–248)0.441
        Urinary output ml, median (IQR)1495 (818–2255)1483 (818–2135)1495 (807–2760)0.783
        Fluid balance ml, median (IQR)2477 (1280–3673)2636 (1525–4278)2412 (1124–2412)0.211
      Laboratory values at admission
        pH, median (IQR)7.17 (7.07–7.23)7.18 (7.03–7.24)7.16 (7.09–7.20)0.683
        Bicarbonate mmol/l, median (IQR)8.70 (6.00–11.60)9.00 (6.05–13.30)8.50 (5.95–10.73)0.212
        Base excess mmol/l, median (IQR)9.30 (6.55–13.45)9.30 (6.00–14.85)9.50 (7.03–12.80)0.537
        Lactate mmol/l, median (IQR)7.55 (4.85–10.33)7.50 (4.35–10.10)8.10 (5.80–10.55)0.475
        Creatinine, mg/dl, median (IQR)1.29 (1.05–1.56)1.27 (0.99–1.56)1.31 (1.31–1.56)0.281
        S100B, µg/l, median (IQR)0.11 (0.07–0.25)0.10 (0.07–0.31)0.13 (0.07–0.25)0.634
        Neuron specific enolase, µg/l, median (IQR)35.30 (15.60–84.30)35.60 (14.00–84.90)30.30 (18.25-74-18)0.891
      Coronary angiography, n (%)49 (62.0)22 (56.4)27 (67.5)0.310
      Coronary revascularization, n (%)40 (50.6)17 (43.6)23 (57.5)0.216
      Abbreviations: COPD: chronic obstructive pulmonary disease, GReg: gastric regurgitation, IQR: interquartile range, n: number, yr: years

      3.2 GReg and neurological outcome

      Among patients with GReg 35 patients (88%) experienced poor neurologic outcome compared to 25 patients (64%) without GReg (p=0.015). In the binary logistic regression model, we identified a significant association of GReg on the first day of hospital admission with poor neurological outcome with a univariable OR of 3.92 (95% CI, 1.25–12.29; p = 0.02). This association was even more pronounced after adjustment for first rhythm non shockable, private location of OHCA and cardiac arrest unwitnessed with an adjusted OR of 5.37 (95% CI 1.41–20.46; p = 0.01) for poor neurological outcome. The area under the ROC curve for GReg on the first day was 0.69 (95% CI, 0.56–0.81) for poor neurological outcome. Univariate, multivariable and ROC analyses of known clinical risk factors of poor neurological outcome in OHCA are summarized in Table 2.
      Table 2Univariate and multivariable models for risk factors associated with poor neurological outcome in in Out-of-Hospital Cardiac Arrest Survivors.
      univariate modelsmultivariable model
      ParameterOR (95% CI)p-value ROCOR (95% CI)p-value
      Gastric regurgitation3.92 (1.25–12.29)0.020.695.37 (1.41–20.46)0.01
      Clinical Confounders
      First rhythm non-shockable9.40 (1.17–75.65)0.040.6512.83 (1.36–120.00)0.03
      Private location of collapse2.65 (0.89–7.90)0.980.620.07
      Cardiac arrest unwitnessed6.00 (0.74–48.8)0.090.600.99
      Age, years
      variable was scaled to 1 standard deviation. Variables with ROC values ≥ 0.60 were selected for further multivariable analysis. Multivariable analysis was adjusted for first rhythm, location of OHCA, cardiac arrest unwitnessed and significant variables were presented by OR and 95%CI. ROSC, return of spontaneous circulation; COPD, chronic obstructive pulmonary disease;
      1.33 (0.80–2.21)0.280.59
      Male Sex0.39 (0.08–1.88)0.240.56
      COPD2.38 (0.27–20.67)0.430.53
      Dose of epinephrine, mg1.04 (0.82–1.30)0.770.52
      Time to ROSC, min
      variable was scaled to 1 standard deviation. Variables with ROC values ≥ 0.60 were selected for further multivariable analysis. Multivariable analysis was adjusted for first rhythm, location of OHCA, cardiac arrest unwitnessed and significant variables were presented by OR and 95%CI. ROSC, return of spontaneous circulation; COPD, chronic obstructive pulmonary disease;
      0.86 (0.51–1.47)0.580.51
      Diabetes mellitus0.84 (0.23–3.04)0.790.49
      History of MI0.84 (0.23–3.04)0.790.48
      Cardiac cause of death0.35 (0.41–2.97)0.330.46
      low asterisk variable was scaled to 1 standard deviation. Variables with ROC values ≥ 0.60 were selected for further multivariable analysis. Multivariable analysis was adjusted for first rhythm, location of OHCA, cardiac arrest unwitnessed and significant variables were presented by OR and 95%CI. ROSC, return of spontaneous circulation; COPD, chronic obstructive pulmonary disease;

      4. Discussion

      The present study identified GReg during the first day of hospital admission after cardiac arrest as strong and independent predictor of poor neurological outcome in comatose OHCA survivors. Patients presenting with GReg were at significant higher risk for poor neurological outcome compared to patients without regurgitation. This novel parameter seems to be an ideal clinical marker for prognostication as GReg is easily available, inexpensive, and routinely measured in ICU patients.
      Delayed gastric emptying and subsequent regurgitation is a common problem in critically ill patients that significantly affects clinical outcome [
      • Alberda C.
      • Gramlich L.
      • Jones N.
      • Jeejeebhoy K.
      • Day A.G.
      • Dhaliwal R.
      • et al.
      The relationship between nutritional intake and clinical outcomes in critically ill patients: results of an international multicenter observational study.
      ,
      • Wurm R.
      • Cho A.
      • Arfsten H.
      • van Tulder R.
      • Wallmuller C.
      • Steininger P.
      • et al.
      Non-occlusive mesenteric ischaemia in out of hospital cardiac arrest survivors.
      ]. This study analyzed for the first time the impact of Greg on neurological outcome. Motor functions of the stomach and esophagus are modulated and controlled by the ANS that provides extrinsic neural inputs, mainly from parasympathetic and sympathetic pathways. Disturbance of this extrinsic innervation may lead to disorganized and dysregulated gastrointestinal activity with relaxation of the lower esophageal sphincter and abnormal motility patterns [
      • Browning K.N.
      • Travagli R.A.
      Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions.
      ]. As hypoxic-ischemic brain injury can affect and disorder the ANS [
      • Lee R.H.
      • Couto E.S.A.
      • Lerner F.M.
      • Wilkins C.S.
      • Valido S.E.
      • Klein D.D.
      • et al.
      Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.
      ,
      • De Raedt S.
      • De Vos A.
      • De Keyser J.
      Autonomic dysfunction in acute ischemic stroke: an underexplored therapeutic area?.
      ,
      • McLaren A.
      • Kerr S.
      • Allan L.
      • Steen I.N.
      • Ballard C.
      • Allen J.
      • et al.
      Autonomic function is impaired in elderly stroke survivors.
      ], it is tempting to speculate that increased GReg reflects dysfunction of the ANS and may be considered as a reliable and early detectable surrogate variable for hypoxic-ischemic brain injury after OHCA. This hypothesis is supported by previous studies showing that dysfunction of the ANS were found associated with non-specific esophageal motility disorders and increased GReg in different patient populations [
      • Pirtniecks A.
      • Smith L.F.
      • Thorpe J.A.
      Autonomic dysfunction in non-specific disorders of oesophageal motility.
      ]. Moreover, the emetic center of the ANS gets input from various sources, e.g. area postrema, nucleus tractus solitarii, cortex and limbic system [
      • Yates B.J.
      • Catanzaro M.F.
      • Miller D.J.
      • McCall A.A.
      Integration of vestibular and emetic gastrointestinal signals that produce nausea and vomiting: potential contributions to motion sickness.
      ]. Hippocampus, a central part of the limbic system, is described as especially vulnerable to hypoxia and could therefore trigger emetic processes in OHCA patients [
      • Encephalopathy L.B.
      a vicious cascade following forebrain ischemia and hypoxia.
      ].
      The increasing rate of OHCA survivors combined with the high uncertainty of neurological outcome [
      • Rea T.D.
      • Eisenberg M.S.
      • Sinibaldi G.
      • White R.D.
      Incidence of EMS-treated out-of-hospital cardiac arrest in the United States.
      ,
      • Atwood C.
      • Eisenberg M.S.
      • Herlitz J.
      • Rea T.D.
      Incidence of EMS-treated out-of-hospital cardiac arrest in Europe.
      ] highlights the continuing clinical need to estimate neurological recovery early after CPR. Early, reliable prognosis within the first days following ROSC is often impossible based on currently available models including clinical assessment and biomarkers. We therefore determined GReg during the first day of hospital admission for prognostication. This study considerably extends the limited knowledge in early neurological outcome prediction using a very simple clinical parameter. Although GReg in this patient population may be influenced by various factors, including medications, hyperglycemia, electrolyte disturbances, mesenteric ischemia, sepsis and the choice of enteral feeding [
      • Landzinski J.
      • Kiser T.H.
      • Fish D.N.
      • Wischmeyer P.E.
      • MacLaren R.
      Gastric motility function in critically ill patients tolerant vs intolerant to gastric nutrition.
      ], we revealed a strong association with poor neurological outcome.
      Limitations: Although results were robust to adjustment for selected potential confounders, we cannot exclude that other, not recorded parameters, including bystander CPR, the specification of witnesses, the time from alarm to defibrillation, the time from alarm to CPR and the time from alarm till vasopressor administration or shock might confound our results. Furthermore, larger studies are needed to analyze whether the implementation of GReg into current prognostication models may improve neurological outcome prediction in comatose OHCA patients. It remains to be assessed how these more and more complex models can be used efficiently in daily clinical practice and in how far machine learning /artificial intelligence may be able to support decision making in the future.

      5. Conclusion

      GReg on the first day after OHCA is an early, strong and independent predictor for neurological outcome in comatose OHCA survivors. These results are particularly compelling because measurement of GReg is inexpensive and routinely performed in all critical care units.

      Declaration of Competing Interest

      The authors declare that there is no conflict of interest.

      Funding

      The authors disclosed receipt of the following financial support for the research, authorship and publication of this article: This project has been funded by the OENB [grant number: #15959] (2014, to CA), a research grant of the Austrian Society of Cardiology (2014, to CA) and the Medical Scientific Fund of the Mayor of the City of Vienna [grant number: #19061] (2019, to CA). The funding bodies played no role in the design of the study and collection, analysis and interpretation of data and in the writing of the manuscript.

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