This document provides an overview of neonatal shock management. It defines neonatal shock and describes the pathophysiology. There are four main types of shock - hypovolemic, distributive, cardiogenic, and obstructive. The document outlines signs and symptoms of shock to look for on clinical evaluation including poor perfusion, tachycardia, hypotension, and organ dysfunction. Initial stabilization steps are described, including respiratory support, vascular access, fluid resuscitation, antibiotics for suspected sepsis, and correcting other physiological disturbances. Ongoing management involves monitoring for response and treating specific underlying conditions. Vasopressors may be needed if shock is not reversing with initial stabilization measures.
4. OBJECTIVES
1- NEONATAL SHOCK EVALUATION ( HOW TO ANTICIPATE ?)
2- INITIAL STABILIZATION (WHAT'S RULES AND STEPS?)
3- ONGOING AND SPECIFIC MANAGEMENT
4- VASOPRESSORS AGENTS ( WHEN AND HOW TO GIVE CORRECTLY?)
5. WHAT'S NEONATAL SHOCK?
SHOCK IS A DYNAMIC AND UNSTABLE PATHOPHYSIOLOGICAL STATE
CHARACTERIZED BY INADEQUATE TISSUE PERFUSION
SHOCK IS OFTEN INITIALLY REVERSIBLE(MUST BE RECOGNIZED AND
TREATED IMMEDIATELY) TO PREVENT PROGRESSIVE IRREVERSIBLE ORGAN
DYSFUNCTION
6. PATHOPHYSIOLOGY OF SHOCK AAP
Oxygen content in the
arterial blood (CaO2)
= 1.36 x Hgb x SaO2
+ (0.0031 x PaO2)
CO = HR x SV
Oxygen delivery (DO2)
= CO x CaO2
BP = CO x SVR
8. SHOCK IS CLASSIFIED BASED ON THE FOLLOWING
MECHANISMS.
1-HYPOVOLEMIC − DUE TO INSUFFICIENT (CO)
2-DISTRIBUTIVE − SEVERELY DECREASED (SVR)
3-CARDIOGENIC − CARDIAC DYSFUNCTION (PUMP FAILURE) OR
ARRHYTHMIA, CAUSING A DECREASE IN CO
4-OBSTRUCTIVE – ( TENSION PNEUMOTHORAX, PPHN, CARDIAC
TAMPONADE, MASSIVE PULMONARY EMBOLISM)
9. HYPOVOLEMIC SHOCK
1-FETOMATERNAL HEMORRHAGE
2- ACUTE HEMORRHAGE FROM UMBILICAL CORD PROLAPSE OR RUPTURE
3-ACUTE BLEEDING INTO THE SUBGALEAL HEMORRHAGE
4-MASSIVE INTERNAL BLEEDING IN THE (GI) TRACT, BRAIN, LUNGS, OR
OTHER MAJOR ORGAN
10. 5-TUMOR ASSOCIATED ACUTE HEMORRHAGE (EG, SACRAL COCCYGEAL
TERATOMA)
6- ACUTE BLOOD TRANSFUSION BETWEEN MONOCHORIONIC TWINS
7-THIRD SPACING AS CAN OCCUR WITH PERINATAL DISTRESS AND ACUTE
INTESTINAL INJURY (EG, VOLVULUS, NECROTIZING ENTEROCOLITIS,
INTESTINAL PERFORATION).
11. DISTRIBUTIVE SHOCK
1-SEPSIS IS THE MOST COMMON CAUSE OF DISTRIBUTIVE SHOCK
2-ADRENAL INSUFFICIENCY
3- TOXIC SHOCK SYNDROME AND HYDROPS FETALIS
14. MULTIFACTORIAL SHOCK
1-SEPSIS – IS TYPICALLY CLASSIFIED AS DISTRIBUTIVE SHOCK. HOWEVER,
MAY BE CARDIOGENIC SHOCK DUE TO MYOCARDIAL DEPRESSION AND
HYPOVOLEMIC SHOCK DUE TO CAPILLARY LEAK AND THIRD SPACING
15. 2-PULMONARY HYPERTENSION – TYPICALLY OBSTRUCTIVE SHOCK.
HOWEVER, WITH SEVERE DISEASE COMMONLY HAVE BIVENTRICULAR
DYSFUNCTION LEADING TO CARDIOGENIC SHOCK
16. 3- HYDROPS FETALIS ‒ TYPICALLY DISTRIBUTIVE SHOCK DUE TO
CAPILLARY LEAK, BUT MAY BE HYPOVOLEMIC SHOCK (EG, THIRD
SPACING), CARDIOGENIC SHOCK (EG, CONGENITAL CARDIAC DISEASE),
AND OBSTRUCTIVE SHOCK (EG, CONGENITAL OBSTRUCTIVE LYMPHATIC
ABNORMALITY)
17.
18. WHAT DO YOU THINK TYPES OF SHOCK IN NEC?
1- DISTRIBUTIVE AND CARDIOGENIC
2- DISTRIBUTIVE AND HYPOVOLEMIC
3-OBSTRUCTIVE AND CARDIOGENIC
4-DISTRUBUTIVE AND OBSTRUCTIVE
21. 2-DLAYED CAPILLARY REFILL >4 SECONDS
-IS SUGGESTIVE OF NEONATAL SHOCK
-THE PREDICTIVE VALUE OF CAPILLARY REFILL IS POOR
-IT IS NOT A RELIABLE PHYSICAL FINDING TO EITHER CONFIRM THE
DIAGNOSIS OF SHOCK OR TO ASSESS RESPONSE TO THERAPY IN NEWBORNS.
-NO DEFINITIVE CORRELATION BETWEEN TISSUE PERFUSION, BP, AND OUTCOME HAS BEEN ESTABLISHED
22. 3-ABNORMAL HEART RATE
.TACHYCARDIA IS A COMMON BUT NONSPECIFIC FINDING IN NEONATAL
SHOCK
.VARIABILITY OF HR MAY BE AN EARLY SIGN OF SEPTIC SHOCK
.IN FT, BRADYCARDIA IS A LATE SIGN OF SHOCK; WHEREAS IN PT MAY BE AN
EARLIER MANIFESTATION OF SHOCK.
23. 4-HYPOTENSION
DEF.
1. MEAN BLOOD PRESSURE <5TH TO 10TH PERCENTILE OF NORMATIVE
BLOOD PRESSURE
2. MEAN BLOOD PRESSURE THAT IS LESS THAN THE GESTATIONAL AGE OF THE
INFANT IN (PT IN THE FIRST 3–5 DAYS OF LIFE)- (BAPM_R)
3. MEAN BLOOD PRESSURE <30 MM HG
24. 4. FOR A RAPID REFERENCE OF PREMATURE AND
TERM INFANT BLOOD PRESSURE RANGES
25. 4-HYPOTENSION
SYSTOLIC HYPOTENSION
IS A MARKER FOR DECREASED CO
DIASTOLIC HYPOTENSION
IS A MARKER FOR DECREASED SVR
THE MEAN BLOOD PRESSURE
IS CONSIDERED THE MOST ACCURATE MEASUREMENT OF SYSTEMIC
PERFUSION PRESSURE
27. YOUR NURSE TOLD YOU THAT WHEN SHE WAS TAKING VITAL SIGNS TO
17-DAYS OLD PT 33WEAKER WEANED SUCCESSFULLY FROM CPAP AFTER
RECEIVING SURFACTANT AND CONSIDER AS A GROWER WITH WEIGHT
1700 GM, HAVING HYPOTENSION MBP 28 FOR 3 TIMES BY
NONINVASIVE METHOD, HR150/MIN, CRT 2 SEC, FEEDING NG 25ML
SATISFACTORY. WITH SKIN MOTTLING. WHAT'S YOUR NEXT ORDER?
1- CHECK U.O.P. AND R.B.S.
2-SAMPLE FOR SERUM LACTATE AND BLOOD GASES
3- START SHOCK THERAPY 10ML/KG FOR 30 MIN
4- START DOPAMINE 5 MIC/KG /MIN
28.
29. EXPLANATION
1-IF THE BLOOD PRESSURE IS LOW BUT THE URINE OUTPUT IS ADEQUATE,
AGGRESSIVE TREATMENT MAY NOT BE NECESSARY AS RENAL PERFUSION IS
ADEQUATE (INDIRECT MEASURE OF END-ORGAN FUNCTION)
2-AN EXCEPTION WOULD BE THE INFANT WITH SEPTIC SHOCK AND
HYPERGLYCEMIA RESULTING IN OSMOTIC DIURESIS AND INCREASED URINE
OUTPUT.
GOMELLA 2020
30. 3- THE LACK OF CLEAR DATA ON THE PREVALENCE OF NEONATAL
HYPOTENSION IS PRIMARILY DUE TO THE UNCERTAINTY ABOUT THE LOWER
LIMIT OF THE GESTATIONAL AGE – A POSTNATAL AGE–DEPENDENT NORMAL
BLOOD PRESSURE RANGE IN NEONATES
AVERY10 EDITION 2018
31. 5- OTHER CLINICAL MANIFESTATIONS
1-NEUROLOGIC:
.IN THE INITIAL STAGES OF SHOCK, NEUROLOGIC CHANGES VARY FROM
LETHARGY (INCLUDING POOR FEEDING) TO IRRITABILITY.
.IN THE LATER STAGES, THERE IS PROGRESSION TO STUPOR OR COMA
OTHER NEUROLOGIC FINDINGS
HYPOTONIA
DIMINISHED DEEP TENDON REFLEXES
ABSENCE OF DEVELOPMENTAL REFLEXES
32. 2-RENAL
. THERE IS A STRONG CORRELATION BETWEEN LOW URINARY OUTPUT
(OLIGURIA) AND LOW SYSTEMIC BLOOD FLOW
. SHOCK WILL RESULT IN RENAL INJURY AND IMPAIRMENT, WHICH IS
MANIFESTED BY INCREASING SERUM CREATININE AND BLOOD UREA
NITROGEN (BUN) LEVELS.
33. 3-RESPIRATORY
•TACHYPNEA SEEN IN INFANTS WITH SEPTIC OR CARDIOGENIC SHOCK AS A
COMPENSATORY RESPONSE TO METABOLIC ACIDOSIS
•PERIODIC BREATHING AND APNEA ARE USUALLY CENTRALLY MEDIATED AND
ARE MORE LIKELY TO BE ASSOCIATED WITH DECREASED CEREBRAL PERFUSION
•HYPOXEMIA MAY BE PRESENT IN INFANTS WITH SHOCK DUE TO CARDIAC
DYSFUNCTION OR OBSTRUCTED BLOOD FLOW.
34. 4-GASTROINTESTINAL
•POOR FEEDING DUE TO LETHARGY AND/OR RESPIRATORY DISTRESS.
•VOMITING AS A MANIFESTATION OF DECREASED MOTILITY , WHICH MAY
PROGRESS TO PARALYTIC ILEUS.
•ABDOMINAL DISTENSION AS A MANIFESTATION OF ILEUS.
35. LABORATORY FINDINGS
1- METABOLIC ACIDOSIS AND AN INCREASE IN LACTATE ( THE MOST COMMON
)
2-ANEMIA IN HEMORRHAGIC HYPOVOLEMIC SHOCK
3-PROLONGED PT/INR/ PTT WITH CONSUMPTIVE COAGULOPATHY WITH
SEPTIC SHOCK , BIRTH ASPHYXIA AND PLACENTAL ABRUPTION (HYPOVOLEMIC
SHOCK)
36. 4-GLUCOSE LEVELS MAY BE ELEVATED OR DECREASED DURING
NEONATAL SHOCK
5- HYPERKALEMIA DUE TO TISSUE INJURY AND CELL DEATH
6- SERUM BILIRUBIN LEVELS AND LIVER ENZYMES DUE TO
HEPATIC INJURY
7- SERUM CREATININE AND BUN MAY BE ELEVATED DUE TO
RENAL INJURY
37. CLINICAL EVALUATION IN BRIEF
.SHOCK IS CLINICALLY BASED ON A CONSTELLATION OF CLINICAL,
BIOCHEMICAL, AND HEMODYNAMIC FEATURES. AND METABOLIC ACIDOSIS.
.THE EARLY STAGES OF SHOCK MAY PRESENT WITH NORMAL(BP) BUT WITH
TACHYCARDIA AND COMPENSATORY PERIPHERAL VASOCONSTRICTION.
.HYPOTENSION IS TYPICALLY FOUND ONLY IN THE LATE STAGES OF SHOCK
AND BRADYCARDIA IS USUALLY OBSERVED IN THE TERMINAL STAGE IN TERM
INFANTS, BUT MAY BE AN EARLY FINDING IN PRETERM INFANTS
40. 2-INITIAL STABILIZATION RULES
1- SUCCESSFUL MANAGEMENT OF NEONATAL SHOCK NEED RAPID
INTERVENTION TO RESTORE PERFUSION REGARDLESS OF UNDERLYING
ETIOLOGY
2- DURING RAPID INTERVENTION FOR STABILIZATION YOU SHOULD DO
EVALUATION TO DETERMINE THE ETIOLOGY IN ORDER TO SUBSEQUENT
MANAGEMENT
41. INITIAL STABILIZATION STEPS
1- RESPIRATORY SUPPORT :
NEONATES IN SHOCK GENERALLY ARE IN RESPIRATORY DISTRESS OR ARE APNEIC
ALMOST ALWAYS REQUIRE POSITIVE PRESSURE VENTILATION, ENDOTRACHEAL
INTUBATION, AND MECHANICAL VENTILATION
42. 2- VASCULAR ACCESS –
VASCULAR ACCESS SHOULD BE ESTABLISHED AND BLOOD SAMPLES OBTAINED FOR
INITIAL TESTING.
IF FEASIBLE, CENTRAL LINES FOR FREQUENT BLOOD DRAWING AND CONSISTENT
VASCULAR ACCESS SHOULD BE CONSIDERED.
43. 3-FLUID RESUSCITATION
. BOLUS IV FLUID OF NORMAL SALINE 0.9% OR RINGER LACTATE IS APPROPRIATE FOR
MOST NEONATAL SHOCK
. THE VOLUME AND RATE OF FLUIDS VARIES ACCORDING TO SUSPECTED ETIOLOGY OF
SHOCK
A-IN SUSPECTED HYPOVOLEMIC SHOCK
20ML/KG NORMAL SALINE WITHIN 15 MIN
ADDITIONAL FLUIDS OR BLOOD TRANSFUSION MAYBE NEEDED IF
THERE IS BLOOD LOSS
44. B- IN SUSPECTED SEPTIC/DISTRIBUTIVE SHOCK
10-20 ML/KG NORMAL SALINE WITHIN 15-30 MIN
C- IN SUSPECTED CARDIOGENIC SHOCK
FLUID BOLUS MAY NOT IMPROVE PERFUSION AND SOME CASES CAUSE MORE
DETERIORATION
D- UNDIFFERENTIATION SHOCK
10ML/KG NORMAL SALINE WITHIN 30 -60 MIN AND MONITOR RESPONSE
45. EXCESSIVE ISOTONIC FLUID ADMINISTRATION (>30 ML/KG) IN
PRETERM INFANTS (<28 WEAK) IS ASSOCIATED WITH AN
INCREASED RISK OF (IVH) AND DEATH.
46. ASSESSING THE RESPONSE TO THE INITIAL FLUID BOLUS (MONITORING HEART
RATE [HR], BLOOD PRESSURE [BP], PERIPHERAL PERFUSION) IS IMPORTANT
TO DETERMINE IF FURTHER FLUID RESUSCITATION
47. (IV) EMPIRIC ANTIBIOTICS ARE ADMINISTERED PENDING RESULTS FROM
BLOOD CULTURES AS NEONATAL SEPSIS IS THE MOST COMMON CAUSE OF
NEONATAL SHOCK
48. 4-OTHER STABILIZATION MEASURES
OTHER PHYSIOLOGICAL DISTURBANCES SHOULD BE CORRECTED INCLUDE
A-ABNORMAL GLUCOSE LEVELS
B-HYPOTHERMIA
C-ELECTROLYTE DISTURBANCES
D-THROMBOCYTOPENIA
E-COAGULOPATHY
49. 3-ONGOING AND SPECIFIC MANAGEMENT
SOME SPECIFIC MANAGEMENTS CANT BE WAITED AND SHOULD BE DONE
CONCOMITANT WITH STABILIZATION MEASURES
1-PNEUMOTHORAX / CARDIAC TAMPONADE– THORACENTESIS/
PERICARDIOCENTESIS
2- CCHD - PGE1 INFUSION
3-ACUTE BLOOD LOSS- RBCS TRANSFUSION
50. NEONATAL SHOCK IS AN EMERGENCY NEED CONTINUOUS MONITORING
1-CONTINUOUS (HR) AND PULSE OXIMETRY MONITORING.
2-FREQUENT BP MONITORING EVERY 15 TO 30 MINUTES.
3-ASSESSMENT EVERY ONE TO TWO HOURS TO EVALUATE CHANGES IN PERFUSION.
51. 4-BLOOD GAS MONITORING EVERY THREE TO FOUR HOURS
5-URINE OUTPUT SHOULD BE MONITORED AT LEAST EVERY FOUR
HOURS.
6-ELECTROLYTE LEVELS, COMPLETE BLOOD COUNTS, AND
COAGULATION STUDIES ARE OFTEN NEEDED SEVERAL TIMES PER DAY
AS WELL
53. YOU HAVE A BABY OF PURELY HYPOVOLEMIC SHOCK DUE TO BLOOD
LOSS FROM CORD AND YOUR BABY TACHYCARDIC, PALLOR, CRT5 SEC
,RD, METABOLIC ACIDOSIS , UNRESPONSIVE AND STILL MAINTAIN BLP .
WHAT'S YOUR SEQUEL ORDERS
1- IV FLUID 20 ML/KG WITHIN 1 HOUR THEN DOPAMINE INFUSION THEN RBCS
TRANSFUSION
2-IV FLUID 20 ML/KG WITHIN 30 MIN AND REPEATED IF NO RESPONSE WITH CLOSE
MONITORING AND DOPAMINE INFUSION
3- RESPIRATORY SUPPORT THEN IV FLUID 20 ML/KG WITHIN 15 MIN CAN BE REPEATED
WITH MONITORING THEN DOPAMINE INFUSION THEN RBCS TRANSFUSION
4- RESPIRATORY SUPPORT WITH IV FLUID 20 ML/KG WITHIN 15 MIN REPEATED
ACCORDING TO RESPONSE WITH CLOSE MONITORING AND RBCS TRANSFUSION
57. 4-VASOPRESSORS AGENTS
1- DOPAMINE
-DOPAMINE USED AS 1ST LINE AGENT IN DISTRIBUTIVE AND CARDIAC SHOCKS
-ITS EFFECT IS INOTROPIC (INCREASE CO) PREDOMINANT AT 5-10 MIC/KG/MIN
-ANOTHER EFFECT IS VASOCONSTRICTIVE (INCREASE SVR) PREDOMINANT MORE
THAN 10MIC/KG/MIN
58. --DOPAMINE STARTED WITH 5 MIC/KG/MIN AND TITRATED ACCORDING TO
RESPONSE
-DOPAMINE HAS UNPREDICTABLE RESPONSE BECAUSE OF ITS CLEARANCE
SHOULD BE MONITORING ACTION
--SOME STUDIES SUGGESTIVE THAT DOPAMINE HAS NEGATIVE (CO) AS
INCREASING SVR
59. 1- BEFORE STARTED DOPAMINE INFUSION YOU SHOULD CORRECT
HYPOVOLEMIA
2- DOPAMINE INFUSION SHOULD INFUSED IN CENTRAL LINE (STRONGLY
RECOMMENDED)
3- DOPAMINE SHOULD BE PREPARED IN STANDARD CONCENTRATION
60. EXAMPLE – BABY 2KG NEED DOPAMINE 5 MIC/KG/MIN
STANDARD CONCENTRATION 1.6MG/ML ( FIXED)
TOTAL VOLUME CAN BE 30 ML ( OPTIONAL AS YOU PREFER )
DOPAMINE AMPULE 40 MG/ML
1ST CALCULATE THE AMOUNT OF DRUG NEEDED PER DEFINED FINAL FLUID VOLUME:
DESIRED FINAL CONCENTRATION (MG/ML) × DEFINED FINAL FLUID VOLUME (ML) = AMOUNT OF
DRUG
1.6 × 30 = 48 MG DOPAMINE NEEDED 48/40(DOPAMINE AMPULE ) = 1.2 ML DOPAMINE
IN 30 ML
YOUR ORDER PREPARATION IS ADD 1.2 ML OF DOPAMINE (40 MG/ML) TO 28.8 ML OF D5W
61. 2ND TO ORDER DOSE IN ML/H
DOSE (MG) ÷ DRUG CONCENTRATION (MG/ML) × 60 = DRUG INFUSION PER HOUR
5MIC/KG/MIN TO 2KKG BABY
.005 MG(DOSE)×2(WEIGHT)/1.6 (STANDARD CONCENTRATION) × 60 (FROM MIN TO
HOUR )= 0.37 ML/H
YOUR ORDER FOR EXAMPLE BABY WILL BE GIVE 0.37ML/H FROM PREPARED 1.2 ML
DOPAMINE IN 28.8 ML G5%
62. 2- DOBUTAMINE
-INTROPES THAT INCREASE (CO) THROUGH INCREASING (HR )AND IMPROVE CARDIAC
CONTRACTILITY
- APPROPRIATE AS 1ST LINE OF MANAGEMENT CARDIAC SHOCK AS ITS INOTROPIC ACTION
- HAS HIGHLY VARIABLE EFFECT ON NEONATAL (BL P) , MAYBE INCREASE OR DECREASE OR NO
EFFECT
- DRUG CLEARANCE VARIABLE AND ITS ACTION OF INCREASING (CO) MUCH BETTER COMPARING
TO DOPAMINE
63. -DOBUTAMINE INFUSION STARTED WITH 5 MIC/KG/MIN AND TITRATED WITH
RESPONSE TILL 20MIC/KG/MIN
-DOBUTAMINE AMPULE 12.5 MG/1ML
-THE STANNARD CONCENTRATION 2MG/1ML
- SAME PREPARATION AND DOSAGE ROLES LIKE DOPAMINE WITH STANDARD DILUTION
2MG/1ML
64. WHAT'S YOUR ORDER IF YOU WANT INFUSED DOBUTAMINE 7.5 MIC/KG/MIN
TO BABY 1.5 KG?
65. ADD 4.8 ML OF DOBUTAMINE (12.5 MG/ML) TO 25.2 ML OF COMPATIBLE
SOLUTION D5 W TO YIELD 30 ML OF INFUSION SOLUTION BY RATE 0.3ML/H
66. 3- EPINEPHRINE
- POTENT INOTROPE (<0.3MIC/KG/MIN)AND INCREASE (SVR) AT HIGH DOSE(
> 0.3MIC/KG/MIN)
- USED AS 2ND LINE OF AGENT IN DISTRIBUTIVE SHOCK OR 1ST LINE AGENT IN
SEVERE CARDIOGENIC SHOCK
- EPINEPHRINE STARTED AT A DOSE OF 0.05 MIC/KG/MIN AND TITRATED UP
INCREMENT 0.01MIC/KG/MIN UP TO 1 MIC/KG/MIN ACCORDING TO
RESPONSE
67. - USE 1MG/1ML CONCENTRATION FOR CONTINUOUS INFUSION PREPARATION
- THE STANDARD CONCENTRATION IS 10 MIC/ 1ML BUT CAN BE GIVEN IN 20,
30, 50 MIC/1 ML
-SAME MANNER IN CALCULATION LIKE DOPAMINE AND DOBUTAMINE
- INFUSION THROUGH CENTRAL LINE IS STRONGLY RECOMMENDED
68. 4- NOREPINEPHRINE
-SECOND OR THIRD LINE IN CARDIOGENIC SHOCK
-MAINLY ALPHA RECEPTOR (↑BP, ↑SVR, ↑PVR)
-INITIAL DOSE, 0.2 - 0.5 MIC/KG/MIN BY IV INFUSION; TITRATE EVERY 30 MINUTES TO
TARGET BLOOD PRESSURE
-STANDARD CONCENTRATION FROM 4 TO 100 MIC/1ML
-INFUSION THROUGH CENTRAL LINE IS STRONGLY RECOMMENDED.
69. 5- HYDROCORTISONE
- USED FOR REFRACTORY SHOCK NOT RESPONDING TO OTHER VASOPRESSOR
AGENTS
- DOSE IS 1MG/KG/DOSE EVERY 8HOURS
70.
71. SOURCES
1- UPTODATE - OCT.,2022
2- AVERY 10TH EDITION -2018
3- GOMELLA IN NEONATOLOGY 8TH EDITION - 2020
4- NEOFAX - 2020
5- MANAGEMENT OF NEONATAL HYPOTENSION AND SHOCK/SEMINAR IN FETAL AND
NEONATAL MEDICINE.
MEDICINE/HTTPS://WWW.SCIENCEDIRECT.COM/SCIENCE/ARTICLE/PII/S1744165X20300469,OCT,2020