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. 2020 Jan 23;18:eRW5055. doi: 10.31744/einstein_journal/2020RW5055
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Epinephrine in pediatric cardiorespiratory arrest: when and how much?

João Carlos Pina Faria 1,2, Camila Augusta Victorino 2, Monica Akemi Sato 1
PMCID: PMC6986458  PMID: 31994613

ABSTRACT

The objective of the present study was to assess the efficacy of different doses, times for infusion of the first dose, intervals of administration of subsequent doses, and number of epinephrine doses in the survival of children and adolescents who went into cardiorespiratory arrest. It is a review study with data from the PubMedⓇ/MEDLINEⓇdatabase. The search was for articles published from January 1st, 2000 to February 10, 2019, with a sample of patients aged under 18 years, published in English, Portuguese and Spanish. We found 222 articles, of which 16 met the inclusion criteria of the study. The first dose should be given as soon as possible. The standard dose (0.01mg/kg) has a better outcome when compared to the higher dose (0.1mg/kg). There is an iⓇverse relation between the number of epinephrine doses and survival. The interval currently recommended between doses has lower survival when compared to larger intervals. The dosage recommended by the American Heart Association presents a better outcome for survival, but the interval between doses and the maximum number of doses should be better assessed.

Keywords: Heart arrest, Out-of-hospital cardiac arrest, Child, Adolescent, Epinephrine/administration & dosage, Survival

INTRODUCTION

Epinephrine was isolated in 1900.1It began to be used for treating cardiorespiratory arrest in the 1960´s.2The American Heart Association (AHA) currently indicates epinephrine to be administered as soon as possible at a dose of 0.01mg/kg (maximum of 1mg), and at 3-to-5-minute intervals between subsequent doses.3The alpha-adrenergic effect, with increase in aortic diastolic pressure and in coronary blood flow, prevails upon standard dose.4

Delay in the administration of epinephrine is associated with decreased survival.5There is a direct relation between time to administration of epinephrine during cardiopulmonary resuscitation for survival in children.6 , 7 When compared to placebo, moderate quality evidence has shown that the standard dose of epinephrine improved return of spontaneous circulation, and survival up to hospital discharge for individuals who had an out-of-hospital cardiac arrest.8

During Advanced Life Support maneuvers using epinephrine, the perfusion pressure of the brain and of other organs remains low, until the return of spontaneous circulation.9 Studies in animals indicate that epinephrine can reduce microcirculation blood flow, which can cause organ damage.10

Considering adults who received epinephrine stratified by rhythms, those non-shockable presented increased survival.11 These rhythms are more frequent in pediatrics.12

Most studies involving epinephrine in cardiorespiratory arrest were performed in adults. American Heart Association recommendations in pediatrics are similar to those for adults, except for dosage of epinephrine, and indication in cardiorespiratory arrest and the same administration time interval remain. It is, however, important to determine if the protocol that is being followed in pediatrics has consequences that may or may not be the most appropriate for patients.

OBJECTIVE

To assess the efficacy of different doses, times for infusion of the first dose, intervals of administration of subsequent doses, and the number of epinephrine doses in the survival of children and adolescents who had an in-hospital or out-of-hospital cardiorespiratory arrest.

METHODS

A systematic literature review was carried out for articles on the PubMed+/MEDLINEⓇ database. The keywords “cardiac arrest”, “children” and “epinephrine”, combined with the “AND” boolean operator were used.

Following, four PubMedⓇ filters were considered: period (Publication date from 2000/01/01 to 2019/02/10), studies in Humans, articles in English, Portuguese or Spanish and age group (child: birth-18 years). Titles and summary of the articles selected were assessed. Studies that assessed the efficacy of epinephrine to treat cardiorespiratory arrest in the pediatric age group were included.

RESULTS

Of the 222 articles found, 126 were excluded upon initial analysis using the four PubMedⓇ filters: 89 studies published before January 1, 2000; 14 studies performed with animals; 14 studies with languages other than English, Spanish or Portuguese; 9 studies performed with patients over 18 years of age.

The remaining 96 articles were assessed. Of these, 95 were in English and one in Spanish. Eighty articles were excluded because they did not describe the efficacy of epinephrine to treat cardiorespiratory arrest in children, regarding survival ( Figure 1 ).

Figure 1. Study flow chart.

Figure 1

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In the second stage, 8 literature reviews, 6 case reports, 3 letters to the editor were excluded, as were 57 studies that did not assess specifically epinephrine in pediatric cardiorespiratory arrest, and 6 were excluded for other reasons.

There were 16 studies5 , 13 - 27 selected among those found on the PubMedⓇ/MEDLINEⓇ database ( Table 1 ). Although there was no search for articles on other databases, all of these articles were cited on the Scopus database, and 15 were cited on the ISI Web of Science database. Only the Anales de Pediatría 27 journal was not present in the ISI Web of Science database. Two studies were randomized clinical trials, and 14 were observational studies.

Table 1. Studies selected for review.

Reference Type of study Type of cardiorespiratory arrest Number of events Objective Conclusion
Fukuda et al.(5) Observational Out-of-hospital 225 Assess time to first epinephrine dose and survival The shorter the time to first epinephrine dose, the higher the survival
Andersen et al.(13) Observational In-hospital 1,558 Assess time to first epinephrine dose with survival and neurological prognosis The shorter the time to first epinephrine dose, the higher the survival, and the better the neurological prognosis
Lin et al.(14) Observational Out-of-hospital trauma 388 Assess time to first epinephrine dose with survival and neurological prognosis Early treatment with epinephrine may not provide benefits in cases of trauma
Hoyme et al.(15) Observational In-hospital 1,630 Assess different intervals between doses of epinephrine and survival Administration intervals longer than those currently recommended present higher survival
Meert et al.(16) Observational Out-of-hospital 295 Assess management during cardiorespiratory arrest with survival and neurological prognosis The higher the number of doses of epinephrine, the lower the survival, and the worse the neurological prognosis
Moler et al.(17) Observational Out-of-hospital 138 Assess different managements to treat cardiorespiratory arrest and survival The higher the number of doses of epinephrine, the lower the survival
de Mos et al.(18) Observational In-hospital 91 Assess different managements to treat cardiorespiratory arrest and survival The higher the number of doses of epinephrine, the lower the survival
Young et al.(19) Observational Out-of-hospital 601 Describe epidemiological characteristics, survival rates and neurological outcomes The higher the number of doses of epinephrine, the lower the survival, and the worse the neurological prognosis
Checchia et al.(20) Observational Out-of-hospital 24 Determine if the measurement of heart troponin I in children in cardiorespiratory arrest outside the hospital anticipates the severity of the myocardial lesion The higher the number of doses of epinephrine, the lower the survival
Donoghue et al.(21) Observational In-hospital not trauma 16,834 (16,245 adults and 537 children) Compare results of cardiopulmonary resuscitation for pediatric patients and adults, and identify factors associated with differences in results between children and adults More epinephrine was used in children In the multivariate analysis, age did not present association regarding survival
Enright et al.(22) Observational Out-of-hospital during physical exercise 9 Determine if long-term survival is influenced by specific resuscitation interventions Children who went into cardiorespiratory arrest during physical exercise present mainly non-shockable rhythms, and epinephrine, in this scenario, may be harmful
Tibballs et al.(23) Observational In-hospital 111 Assess the impact of different factors in prognosis of cardiorespiratory arrest in children Doses of epinephrine above 0.015mg/kg present lower survival
Perondi et al.(24) Randomized In-hospital 68 Compare efficacy between standard dose and high dose of epinephrine in hospital pediatric cardiorespiratory arrest Data suggest that treatment with high doses may be worse than treatment with standard dose
Guay et al.(25) Observational In-hospital 203 Assess efficacy of advanced life support interventions in pediatric cardiorespiratory arrest For epinephrine administered by the intravenous route, the standard dose of 0.01mg/kg seems appropriate as an initial dose
Patterson et al.(26) Randomized Out-of-hospital 230 Assess if a high dose of epinephrine used during out-of-hospital cardiorespiratory arrest refractory to pre-hospital interventions improves return of spontaneous circulation, survival and neurological prognosis A high-dose of epinephrine does not improve or decrease return of spontaneous circulation, survival and neurological prognosis in comparison with standard dose in out-of-hospital cardiorespiratory arrest
Rodríguez Núñez et al.(27) Observational Intra and out-of-hospital 92 Assess the impact on survival of epinephrine (intravenous or intraosseous) in high-dose in comparison to standard dose in children in cardiorespiratory arrest There was no difference in the two groups regarding return of spontaneous circulation, total resuscitation time, neurological status at the end of the episode and survival to hospital discharge and in 1-year follow-up
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DISCUSSION

The relevant aspects for the comparison of articles found in the literature using the chosen keywords are the following:

Time to administration of first epinephrine dose

Three studies assessed if time to administration of first epinephrine dose influenced survival.

Fukuda et al., analyzed 225 children between 1 and 17 years of age who had an out-of-hospital cardiorespiratory arrest in Japan, using retrospective data. There was a direct relation between shorter time to administration of epinephrine and higher 30-day survival (p<0.0001).5

Andersen et al., assessed 1,558 children aged under 18 years, who had an in-hospital cardiorespiratory arrest in the United States, in a retrospective cohort. Similar to the previous study, there was also a relation between shorter time to administration and higher survival (p<0.001).13 The authors also reported that the neurological prognosis was better in the group with shorter time to administration.13However, Lin et al., observed that time to the first dose of epinephrine did not influence survival or neurological prognosis, when they studied 388 children aged under 18 years, seen at 3 emergency centers of Taiwan (p=0.234).14

The different studies that assessed time to administration of first epinephrine dose were carried out with an expressive number of children, albeit ages varied from infants to 18 years. In the study of Fukuda et al.,5 there was a predominance of adolescents over 12 years (76.9%). The study of Andersen et al.,13 comprised a sample of children with a median age of 9 months. Lin et al.,14 included 63.4% of children and adolescents aged over 10 years. Despite the wide range of age groups in the different studies, the factor did not seem to be a determinant of the differences observed in the study by Lin et al.,14 in comparison to those of Fukuda et al.,5 and Andersen et al.13 Therefore, the rationale for this conflicting result is the fact that the study of Lin et al.,14 only assessed out-of-hospital cardiorespiratory arrest secondary to trauma, while the other two studies assessed all causes of cardiorespiratory arrest.

A study performed with 35,065 adults who went into a non-trauma out-of-hospital cardiorespiratory arrest showed that when Advanced Life Support (epinephrine, airway establishment and manual defibrillation) began early, there was higher survival of victims, when compared to Basic Life Support (cardiopulmonary resuscitation and automatic external defibrillator).28

Time interval between doses of epinephrine

A retrospective review of the AHA Get With The GuidelinesⓇ-Resuscitation registry, with 1,630 children aged under 18 years, who had an in-hospital cardiorespiratory arrest, showed that intervals between epinephrine doses longer (>5 to <8 minutes, and 8 to <10 minutes) than those currently recommended by the AHA attained better results in survival to hospital discharge.15A study performed in 2014 in an adult population found similar results after assessing 20,909 in-hospital cardiorespiratory arrest.29

Although an important finding with a high number sample, it is the only study up to present in the literature showing findings different from those recommended.

Number of doses of epinephrine administered

Seven studies found an inverse relation between number of doses of epinephrine and survival.

Data of the Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital Trial on 36 pediatric intensive care units (ICU) in Canada and the United States, with 295 children over 48 hours of life and under 18 years of age who had an out-of-hospital cardiorespiratory arrest were submitted to secondary analysis. The study showed 80% survival when epinephrine did not have to be administered, 54% with one dose, 41% with two doses, 38% with three doses, 36% with four doses, 11% with five or more doses.16 This study found the same relation between the number of doses and the neurological prognosis defined by the second edition of the Vineland Adaptive Behavior Scales (VABS-II).16

A retrospective cohort, with 138 children with more than 24 hours of life and under 18 years, at 15 hospitals, victims of out-of-hospital cardiorespiratory arrest, showed that the number of doses of epinephrine was inversely associated with hospital discharge (p<0.01).17 Only seven of the 46 patients who received more than three doses of epinephrine survived.17 The maximum number of doses of adrenalin received by a normal survivor was five.17

A retrospective study with 91 children under 18 years who had a cardiorespiratory arrest in the pediatric ICU showed that the survival of children who received from two to three doses was 48%, and 13% for those who received four or more doses.18

The secondary analysis of data of a prospective study carried out from 1994 to 1997 assessed 601 out-of-hospital cardiorespiratory arrest in children under 12 years, in two cities in California.19 Children who received more than three doses of epinephrine or more than 31 minutes of cardiopulmonary resuscitation did not survive.19

A prospective observational study on 24 children, aged between 8 months and 17 years, admitted to the pediatric ICU and who had an out-of-hospital cardiorespiratory arrest, concluded that survivors received 1.3 +/- 2.2 doses of epinephrine in comparison to 2.9 +/- 1.6 doses received by non-survivors (p=0.02).20

A retrospective 10-year cohort assessed 16,834 non-trauma cardiorespiratory arrest (537 in children) seen at the Emergency Room.21 The median dose of epinephrine was 3 (zero to 15) in children, and 2 (zero to 9) in adults (p<0.001).21Adults presented more frequent return of spontaneous circulation (53% versus 47%; p=0.02), 24-hour survival (35% versus 30%; p=0.02) and survival to discharge (23% versus 20%; p=NS); however, in the multivariate analysis, age did not associate with outcomes.21

An assumption to explain lower survival with increase in the number of doses of epinephrine is that, the longer cardiorespiratory arrest time, the more doses are administered. Thus, lower survival may be related to duration of cardiorespiratory arrest and not necessarily to an adverse effect of the drug. Another factor that may also contribute to survival of children victims of cardiorespiratory arrest is heart rhythm. Children who initially presented a shockable rhythm cardiorespiratory arrest had higher survival.30 A prospective observational study carried out in Sidney observed nine children under 16 years of age, who had an out-of-hospital cardiorespiratory arrest during physical activity.22The six survivors had a shockable rhythm cardiorespiratory arrest and five of them did not receive epinephrine. The three that died had non-shockable rhythm cardiorespiratory arrest.22 Despite the findings of this study, the number of children assessed was very limited, which did not render an appropriate statistical analysis to reach conclusions that may be reflected population wise.

Dosage of epinephrine administered

Five studies that assessed the relation between the dose of epinephrine administered and survival were found. Three concluded that the standard dose (0.01mg/kg) attains better results. Two concluded that the standard dose or doses above standard have the same survival outcome. No study has shown improvement in survival with super dosages of epinephrine.

A prospective study with 111 children concluded that doses above 0.015mg/kg administered for non-shockable rhythms may lead to secondary ventricular fibrillation, which has a worse outcome than primary ventricular fibrillation.23

A prospective, randomized, double-blind study compared high-doses of epinephrine (0.1mg/kg) with the standard dose of epinephrine as salvage therapy for hospital cardiorespiratory arrest in children after failure of an initial standard dose (n=68).24 The two treatment groups did not differ significantly in terms of return of spontaneous circulation rate (which occurred in 20 patients in the high-dose group, and in 21 in the standard dose group).24 However, the 24-hour survival rate was lower in the high dose epinephrine group as salvage therapy in comparison to the standard dose group.24One of the 34 patients of the high-dose group survived 24 hours, in contrast to 7 of the 34 standard dose patient group (p=0.05).24

A retrospective study compared standard dose, low doses and high doses of epinephrine in pediatric cardiorespiratory arrest. There was no immediate survival or after 24 hours in the group that received a dose below 0.0018mg/kg.25In the group that received doses above standard, there was no immediate survival in children who received more than 0.0357mg/kg, and there were no survivors in 24 hours among children who received a dose above 0.019mg/kg.25

A multicenter randomized controlled study conducted in seven hospitals with 230 patients under 22 years compared the standard dose (n=86) with a dose ten-fold higher of epinephrine (n=127).26There was no statistically significant difference between both groups regarding outcome (return of spontaneous circulation, 24-hour survival, survival to discharge and neurological prognosis).26

A multicenter prospective study analyzed 92 children between 7 days of life and 17 years, victims of cardiorespiratory arrest, in two groups.27 The first group (n=12) received standard doses of epinephrine while the second (n=80) received the standard dose first, and the remaining doses ten-fold higher.27 There was no difference between the two groups regarding return of spontaneous circulation, total resuscitation time, neurological status at the end of the episode, and survival to hospital discharge and in the one-year follow-up.27 The studies assessed in this review showed no advantages in changing the standard dose recommended by the AHA.

CONCLUSION

There are few articles published assessing the use of epinephrine in pediatrics. After assessing the studies of this review, we have concluded that epinephrine should be administered in cardiorespiratory arrest in children as soon as possible. The dose should be standard (0.01mg/kg). Despite studies having showed lower survival with increase in number of epinephrine doses, the fact can be explained by other reasons, such as cardiopulmonary resuscitation time and the initial rhythm of the cardiorespiratory arrest. Only one study assessed the interval between doses of epinephrine and concluded that the interval currently recommended (3 to 5 minutes) leads to lower survival when compared to longer intervals, as it has already been demonstrated for adults, suggesting that less epinephrine (cumulative dose or frequency) can be beneficial in in-hospital pediatric cardiorespiratory arrest.

More studies, preferably randomized clinical trials, need to be performed to better understand how to adjust intervals and maximum number of doses of epinephrine.

REFERENCES

  • 1.. Sneader W. The discovery and synthesis of epinephrine. Drug News Perspect. 2001;14(8):491-4. [DOI] [PubMed]; Sneader W. The discovery and synthesis of epinephrine. Drug News Perspect. 2001;14(8):491–494. doi: 10.1358/dnp.2001.14.8.858417. [DOI] [PubMed] [Google Scholar]
  • 2.. Callaway CW, Donnino MW. Testing Epinephrine for Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):787-88. [DOI] [PubMed]; Callaway CW, Donnino MW. Testing Epinephrine for Out-of-Hospital Cardiac Arrest. N Engl J Med. 2018;379(8):787–788. doi: 10.1056/NEJMe1808255. [DOI] [PubMed] [Google Scholar]
  • 3.. American Heart Association. Web-based integrated guidelines for cardiopulmonary resuscitation and emergency cardiovascular Care – Part 12: Pediatric Advanced Life Support [Internet]. Dallas: (TX); 2015 [cited 2018 Nov 7]. Available from: https://eccguidelines.heart.org/wp-content/themes/eccstaging/dompdf-master/pdffiles/part-12-pediatric-advanced-life-support.pdf; American Heart Association . Web-based integrated guidelines for cardiopulmonary resuscitation and emergency cardiovascular Care – Part 12: Pediatric Advanced Life Support. Dallas: (TX): 2015. [cited 2018 Nov 7]. Internet. https://eccguidelines.heart.org/wp-content/themes/eccstaging/dompdf-master/pdffiles/part-12-pediatric-advanced-life-support.pdf. [Google Scholar]
  • 4.. Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton TJ, et al. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA. 1991;265(9):1139-44. [PubMed]; Paradis NA, Martin GB, Rosenberg J, Rivers EP, Goetting MG, Appleton TJ, et al. The effect of standard- and high-dose epinephrine on coronary perfusion pressure during prolonged cardiopulmonary resuscitation. JAMA. 1991;265(9):1139–1144. [PubMed] [Google Scholar]
  • 5.. Fukuda T, Kondo Y, Hayashida K, Sekiguchi H, Kukita I. Time to epinephrine and survival after paediatric out-of-hospital cardiac arrest. Eur Heart J Cardiovasc Pharmacother. 2018;4(3):144-51. [DOI] [PubMed]; Fukuda T, Kondo Y, Hayashida K, Sekiguchi H, Kukita I. Time to epinephrine and survival after paediatric out-of-hospital cardiac arrest. Eur Heart J Cardiovasc Pharmacother. 2018;4(3):144–151. doi: 10.1093/ehjcvp/pvx023. [DOI] [PubMed] [Google Scholar]
  • 6.. Hansen M, Schmicker RH, Newgard CD, Grunau B, Scheuermeyer F, Cheskes S, Vithalani V, Alnaji F, Rea T, Idris AH, Herren H, Hutchison J, Austin M, Egan D, Daya M; Resuscitation Outcomes Consortium Investigators. Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. Circulation. 2018; 137(19):2032-40. [DOI] [PMC free article] [PubMed]; Hansen M, Schmicker RH, Newgard CD, Grunau B, Scheuermeyer F, Cheskes S, Vithalani V, Alnaji F, Rea T, Idris AH, Herren H, Hutchison J, Austin M, Egan D, Daya M, Resuscitation Outcomes Consortium Investigators Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. Circulation. 2018;137(19):2032–2040. doi: 10.1161/CIRCULATIONAHA.117.033067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.. Raymond TT, Praestgaard A, Berg RA, Nadkarni VM, Parshuram CS; American Heart Association’s Get With The Guidelines-Resuscitation Investigators. The Association of Hospital Rate of Delayed Epinephrine Administration With Survival to Discharge for Pediatric Nonshockable In-Hospital Cardiac Arrest. Pediatr Crit Care Med. 2019;20(5):405-16. [DOI] [PubMed]; Raymond TT, Praestgaard A, Berg RA, Nadkarni VM, Parshuram CS, American Heart Association’s Get With The Guidelines-Resuscitation Investigators The Association of Hospital Rate of Delayed Epinephrine Administration With Survival to Discharge for Pediatric Nonshockable In-Hospital Cardiac Arrest. Pediatr Crit Care Med. 2019;20(5):405–416. doi: 10.1097/PCC.0000000000001863. [DOI] [PubMed] [Google Scholar]
  • 8.. Finn J, Jacobs I, Williams TA, Gates S, Perkins GD. Adrenaline and vasopressin for cardiac arrest. Cochrane Database of Syst Rev. 2019;1:CD003179. [DOI] [PMC free article] [PubMed]; Finn J, Jacobs I, Williams TA, Gates S, Perkins GD. Adrenaline and vasopressin for cardiac arrest. Cochrane Database of Syst Rev. 2019;1:CD003179. doi: 10.1002/14651858.CD003179.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.. Nolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Böttiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Hoek TV. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79(3):350-79. [DOI] [PubMed]; Nolan JP, Neumar RW, Adrie C, Aibiki M, Berg RA, Böttiger BW, Callaway C, Clark RS, Geocadin RG, Jauch EC, Kern KB, Laurent I, Longstreth WT, Merchant RM, Morley P, Morrison LJ, Nadkarni V, Peberdy MA, Rivers EP, Rodriguez-Nunez A, Sellke FW, Spaulding C, Sunde K, Hoek TV. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation. 2008;79(3):350–379. doi: 10.1016/j.resuscitation.2008.09.017. [DOI] [PubMed] [Google Scholar]
  • 10.. Gough CJ, Nolan JP. The role of adrenaline in cardiopulmonar resuscitation. Critical Care. 2018;22(1):139. Review. [DOI] [PMC free article] [PubMed]; Gough CJ, Nolan JP. The role of adrenaline in cardiopulmonar resuscitation. 139Critical Care. 2018;22(1) doi: 10.1186/s13054-018-2058-1. Review. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.. Morales-Cané I, Valverde-León MR, Rodríguez-Borrego MA. Epinephrine in cardiac arrest: systematic review and meta-analysis. Rev Lat Am Enfermagem. 2016;24:e2821. Review. [DOI] [PMC free article] [PubMed]; Morales-Cané I, Valverde-León MR, Rodríguez-Borrego MA. Epinephrine in cardiac arrest: systematic review and meta-analysis. Rev Lat Am Enfermagem. 2016;24:e2821. doi: 10.1590/1518-8345.1317.2821. Review. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.. Ortega AC, Galán CR, Álvarez AC, Cid JL, Dominguéz MA. Reanimación cardiopulmonar avanzada em pediatria / Pediatric advanced life support. An Pedriatr (Barc). 2016;65(4):342-63. [DOI] [PubMed]; Ortega AC, Galán CR, Álvarez AC, Cid JL, Dominguéz MA. An Pedriatr. 4. Vol. 65. Barc: 2016. Reanimación cardiopulmonar avanzada em pediatria / Pediatric advanced life support; pp. 342–363. [DOI] [PubMed] [Google Scholar]
  • 13.. Andersen LW, Berg KM, Saindon BZ, Massaro JM, Raymond TT, Berg RA, Nadkarni VM, Donnino MW; American Heart Association Get With the Guideline-Resuscitation Investigators. Time to Epinephrine and Survival After Pediatric In-Hospital Cardiac Arrest. JAMA. 2015;314(8):802-10. [DOI] [PMC free article] [PubMed]; Andersen LW, Berg KM, Saindon BZ, Massaro JM, Raymond TT, Berg RA, Nadkarni VM, Donnino MW, American Heart Association Get With the Guideline-Resuscitation Investigators Time to Epinephrine and Survival After Pediatric In-Hospital Cardiac Arrest. JAMA. 2015;314(8):802–810. doi: 10.1001/jama.2015.9678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.. Lin YR, Syue YJ, Buddhakosai W, Lu HE, Chang CF, Chang CY, et al. Impact of Different Initial Epinephrine Treatment Time Points on the Early Postresuscitative Hemodynamic Status of Children With Traumatic Out-of-hospital Cardiac Arrest. Medicine (Baltimore). 2016;95(12):e3195. [DOI] [PMC free article] [PubMed]; Lin YR, Syue YJ, Buddhakosai W, Lu HE, Chang CF, Chang CY, et al. Medicine. 12. Vol. 95. Baltimore: 2016. Impact of Different Initial Epinephrine Treatment Time Points on the Early Postresuscitative Hemodynamic Status of Children With Traumatic Out-of-hospital Cardiac Arrest; e3195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.. Hoyme DB, Patel SS, Samson RA, Raymond TT, Nadkarni VM, Gaies MG, Atkins DL; American Heart Association Get With the Guidelines-Resuscitation Investigators. Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest. Resuscitation. 2017;117:18-23. [DOI] [PubMed]; Hoyme DB, Patel SS, Samson RA, Raymond TT, Nadkarni VM, Gaies MG, Atkins DL, American Heart Association Get With the Guidelines-Resuscitation Investigators Epinephrine dosing interval and survival outcomes during pediatric in-hospital cardiac arrest. Resuscitation. 2017;117:18–23. doi: 10.1016/j.resuscitation.2017.05.023. [DOI] [PubMed] [Google Scholar]
  • 16.. Meert KL, Telford R, Holubkov R, Slomine BS, Christensen JR, Dean JM, Moler FW; Therapeutic Hypothermia After Pediatric Cardiac Arrest (Thapca) Trial Investigators. Pediatric Out-of-Hospital Cardiac Arrest Characteristics and Their Association With Survival and Neurobehavioral Outcome. Pediatr Crit Care Med. 2016;17(12):e543-e550. [DOI] [PMC free article] [PubMed]; Meert KL, Telford R, Holubkov R, Slomine BS, Christensen JR, Dean JM, Moler FW, Therapeutic Hypothermia After Pediatric Cardiac Arrest (Thapca) Trial Investigators Pediatric Out-of-Hospital Cardiac Arrest Characteristics and Their Association With Survival and Neurobehavioral Outcome. Pediatr Crit Care Med. 2016;17(12):e543–e550. doi: 10.1097/PCC.0000000000000969. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.. Moler FW, Donaldson AE, Meert K, Brilli RJ, Nadkarni V, Shaffner DH, Schleien CL, Clark RS, Dalton HJ, Statler K, Tieves KS, Hackbarth R, Pretzlaff R, van der Jagt EW, Pineda J, Hernan L, Dean JM; Pediatric Emergency Care Applied Research Network. Multicenter cohort study of out-of-hospital pediatric cardiac arrest. Crit Care Med. 2011;39(1):141-9. [DOI] [PMC free article] [PubMed]; Moler FW, Donaldson AE, Meert K, Brilli RJ, Nadkarni V, Shaffner DH, Schleien CL, Clark RS, Dalton HJ, Statler K, Tieves KS, Hackbarth R, Pretzlaff R, van der Jagt EW, Pineda J, Hernan L, Dean JM, Pediatric Emergency Care Applied Research Network Multicenter cohort study of out-of-hospital pediatric cardiac arrest. Crit Care Med. 2011;39(1):141–149. doi: 10.1097/CCM.0b013e3181fa3c17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.. de Mos N, van Litsenburg RR, McCrindle B, Bohn DJ, Parshuram CS. Pediatric in-intensive-care-unit cardiac arrest: incidence, survival, and predictive factors. Crit Care Med. 2006;34(4):1209-15. [DOI] [PubMed]; Mos N, van Litsenburg RR, McCrindle B, Bohn DJ, Parshuram CS. Pediatric in-intensive-care-unit cardiac arrest: incidence, survival, and predictive factors. Crit Care Med. 2006;34(4):1209–1215. doi: 10.1097/01.CCM.0000208440.66756.C2. [DOI] [PubMed] [Google Scholar]
  • 19.. Young KD, Gausche-Hill M, McClung CD, Lewis RJ. A prospective, population-based study of the epidemiology and outcome of out-of-hospital pediatric cardiopulmonary arrest. Pediatrics. 2004;114(1):157-64. [DOI] [PubMed]; Young KD, Gausche-Hill M, McClung CD, Lewis RJ. A prospective, population-based study of the epidemiology and outcome of out-of-hospital pediatric cardiopulmonary arrest. Pediatrics. 2004;114(1):157–164. doi: 10.1542/peds.114.1.157. [DOI] [PubMed] [Google Scholar]
  • 20.. Checchia PA, Sehra R, Moynihan J, Daher N, Tang W, Weil MH. Myocardial injury in children following resuscitation after cardiac arrest. Resuscitation. 2003;57(2):131-7. [DOI] [PubMed]; Checchia PA, Sehra R, Moynihan J, Daher N, Tang W, Weil MH. Myocardial injury in children following resuscitation after cardiac arrest. Resuscitation. 2003;57(2):131–137. doi: 10.1016/s0300-9572(03)00003-0. [DOI] [PubMed] [Google Scholar]
  • 21.. Donoghue AJ, Abella BS, Merchantc R, Praestgaardd A, Topjiana A, Berg R, Nadkarni V; American Heart Association’s Get With the Guidelines-Resuscitation Investigators. Cardiopulmonary resuscitation for in-hospital events in the emergency department: A comparison of adult and pediatric outcomes and care processes. Resuscitation. 2015;92:94-100. [DOI] [PMC free article] [PubMed]; Donoghue AJ, Abella BS, Merchantc R, Praestgaardd A, Topjiana A, Berg R, Nadkarni V, American Heart Association’s Get With the Guidelines-Resuscitation Investigators Cardiopulmonary resuscitation for in-hospital events in the emergency department: A comparison of adult and pediatric outcomes and care processes. Resuscitation. 2015;92:94–100. doi: 10.1016/j.resuscitation.2015.04.027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.. Enright K, Turner C, Roberts P, Cheng N, Browne G. Primary cardiac arrest following sport or exertion in children presenting to an emergency department: chest compressions and early defibrillation can save lives, but is intravenous epinephrine always appropriate? Pediatr Emerg Care. 2012;28(4):336-9. [DOI] [PubMed]; Enright K, Turner C, Roberts P, Cheng N, Browne G. Primary cardiac arrest following sport or exertion in children presenting to an emergency department: chest compressions and early defibrillation can save lives, but is intravenous epinephrine always appropriate? Pediatr Emerg Care. 2012;28(4):336–339. doi: 10.1097/PEC.0b013e31824d8c78. [DOI] [PubMed] [Google Scholar]
  • 23.. Tibballs J, Kinney S. A prospective study of outcome of in-patient paediatric cardiopulmonary arrest. Resuscitation. 2006;71(3):310-8. [DOI] [PubMed]; Tibballs J, Kinney S. A prospective study of outcome of in-patient paediatric cardiopulmonary arrest. Resuscitation. 2006;71(3):310–318. doi: 10.1016/j.resuscitation.2006.05.009. [DOI] [PubMed] [Google Scholar]
  • 24.. Perondi MB, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350(17):1722-30. [DOI] [PubMed]; Perondi MB, Reis AG, Paiva EF, Nadkarni VM, Berg RA. A comparison of high-dose and standard-dose epinephrine in children with cardiac arrest. N Engl J Med. 2004;350(17):1722–1730. doi: 10.1056/NEJMoa032440. [DOI] [PubMed] [Google Scholar]
  • 25.. Guay J, Lortie L. An evaluation of pediatric in-hospital advanced life support interventions using the pediatric Utstein guidelines: a review of 203 cardiorespiratory arrests. Can J Anaesth. 2004;51(4):373-8. [DOI] [PubMed]; Guay J, Lortie L. An evaluation of pediatric in-hospital advanced life support interventions using the pediatric Utstein guidelines: a review of 203 cardiorespiratory arrests. Can J Anaesth. 2004;51(4):373–378. doi: 10.1007/BF03018242. [DOI] [PubMed] [Google Scholar]
  • 26.. Patterson MD, Boenning DA, Klein BL, Fuchs S, Smith KM, Hegenbarth MA, et al. The use of high-dose epinephrine for patients with out-of-hospital cardiopulmonary arrest refractory to prehospital interventions. Pediatr Emerg Care. 2005;21(4):227-37. [DOI] [PubMed]; Patterson MD, Boenning DA, Klein BL, Fuchs S, Smith KM, Hegenbarth MA, et al. The use of high-dose epinephrine for patients with out-of-hospital cardiopulmonary arrest refractory to prehospital interventions. Pediatr Emerg Care. 2005;21(4):227–237. doi: 10.1097/01.pec.0000161468.12218.02. [DOI] [PubMed] [Google Scholar]
  • 27.. Rodríguez Núñez A, García C, López-Herce Cid J; Grupo de Estudio de la Parada Cardiorrespiratoria en Pediatría. [Is high-dose epinephrine justified in cardiorespiratory arrest in children?] An Pediatr (Barc). 2005;62(2):113-6. Spanish. [DOI] [PubMed]; Rodríguez Núñez A, García C, López-Herce Cid J, Grupo de Estudio de la Parada Cardiorrespiratoria en Pediatría . An Pediatr. 2. Vol. 62. Barc: 2005. Is high-dose epinephrine justified in cardiorespiratory arrest in children? pp. 113–116. Spanish. [DOI] [PubMed] [Google Scholar]
  • 28.. Kurz MC, Schmickerb RH, Leroux B, Nichol G, Aufderheide TP, Cheskes S, Grunau B, Jasti J, Kudenchuk P, Vilke GM, Buick J, Wittwer L, Sahni R, Straight R, Wang HE; ROC Investigators. Advanced vs. Basic Life Support in the Treatment of Out-of-Hospital Cardiopulmonary Arrest in the Resuscitation Outcomes Consortium. Resuscitation. 2018;128:132-7. [DOI] [PubMed]; Kurz MC, Schmickerb RH, Leroux B, Nichol G, Aufderheide TP, Cheskes S, Grunau B, Jasti J, Kudenchuk P, Vilke GM, Buick J, Wittwer L, Sahni R, Straight R, Wang HE, ROC Investigators Advanced vs. Basic Life Support in the Treatment of Out-of-Hospital Cardiopulmonary Arrest in the Resuscitation Outcomes Consortium. Resuscitation. 2018;128:132–137. doi: 10.1016/j.resuscitation.2018.04.031. [DOI] [PubMed] [Google Scholar]
  • 29.. Warren SA, Huszti E, Bradley SM, Chan PS, Bryson CL, Fitzpatrick AL, Nichol G; American Heart Association´s get With the Guideline-Resuscitation (Nacional Registry of CPR) Investigators. Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation. 2014;85(3):350-8. [DOI] [PMC free article] [PubMed]; Warren SA, Huszti E, Bradley SM, Chan PS, Bryson CL, Fitzpatrick AL, Nichol G, American Heart Association´s get With the Guideline-Resuscitation (Nacional Registry of CPR) Investigators Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation. 2014;85(3):350–358. doi: 10.1016/j.resuscitation.2013.10.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.. Nehme Z, Namachivayam S, Forrest A, Butt W, Bernard S, Smith K. Trends in the incidence and outcome of paediatric out-of-hospital cardiac arrest: a 17-year observational study. Resuscitation. 2018;128:43-50. [DOI] [PubMed]; Nehme Z, Namachivayam S, Forrest A, Butt W, Bernard S, Smith K. Trends in the incidence and outcome of paediatric out-of-hospital cardiac arrest: a 17-year observational study. Resuscitation. 2018;128:43–50. doi: 10.1016/j.resuscitation.2018.04.030. [DOI] [PubMed] [Google Scholar]
Einstein (Sao Paulo). 2020 Jan 23;18:eRW5055. [Article in Portuguese]

Epinefrina na parada cardiorrespiratória pediátrica: quando e quanto?

João Carlos Pina Faria 1,2, Camila Augusta Victorino 2, Monica Akemi Sato 1

RESUMO

O objetivo deste estudo foi avaliar a eficácia de diferentes doses, tempos para infusão da primeira dose, intervalos de administração de doses subsequentes e número de doses de epinefrina na sobrevida de crianças e adolescentes que sofreram parada cardiorrespiratória. Trata-se de estudo de revisão, cujas buscas foram feitas na base de dados PubMedⓇ/MEDLINEⓇ. Foram selecionados artigos publicados de 1° de janeiro de 2000 até 10 de fevereiro de 2019, realizados em menores de 18 anos de idade, publicados em inglês, português e espanhol. Foram encontrados 222 artigos, dos quais 16 atenderam os critérios de inclusão no estudo. A primeira dose deve ser aplicada o mais rápido possível. A dose padrão (0,01mg/kg) apresenta melhor desfecho quando comparada à dose alta (0,1mg/kg). Houve relação inversa entre número de doses de epinefrina e sobrevida. O intervalo entre doses recomendado atualmente apresenta menor sobrevida quando comparado a intervalos maiores. A dose recomendada pela American Heart Association apresenta melhor desfecho para sobrevida, porém o intervalo entre doses e o número máximo de doses devem ser melhor avaliados.

Keywords: Parada cardíaca, Parada cardíaca extra-hospitalar, Criança, Adolescente, Epinefrina/administração & dosagem, Sobrevida

INTRODUÇÃO

A epinefrina foi isolada em 1900.1Na década de 1960, passou a ser utilizada para o tratamento da parada cardiorrespiratória.2Atualmente, a American Heart Association (AHA) indica que a epinefrina deve ser administrada o mais rápido possível, na dosagem de 0,01mg/kg (máximo 1mg), e com intervalos de 3 a 5 minutos entre as doses subsequentes.3Na dose padrão, predomina o efeito alfa-adrenérgico, com aumento da pressão diastólica aórtica e do fluxo sanguíneo coronariano.4

O atraso na administração de epinefrina está associado com diminuição da sobrevida.5Há relação direta entre o tempo para a administração da epinefrina durante a ressuscitação cardiopulmonar com a sobrevida da criança.6 , 7Comparado ao placebo, evidências de qualidade moderada mostraram que a epinefrina, na dose padrão, melhorou o retorno da circulação espontânea, e a sobrevivência até a alta hospitalar em pessoas com parada cardíaca extra-hospitalar.8

Durante as manobras do Suporte Avançado de Vida com o uso de epinefrina, a pressão de perfusão cerebral e de outros órgãos permanece baixa, até o retorno da circulação espontânea.9Estudos com animais indicam que a epinefrina pode reduzir o fluxo sanguíneo na microcirculação, o que pode causar lesões nos órgãos.10

Em adultos que receberam epinefrina estratificados por ritmos, os não desfibriláveis tiveram aumento na sobrevida.11Estes ritmos são os mais frequentes em pediatria.12

A maior parte das pesquisas envolvendo epinefrina na parada cardiorrespiratória foi realizada em adultos. As recomendações da AHA em pediatria são semelhantes às de adultos, exceto pela dosagem de epinefrina, mantendo-se a indicação em parada cardiorrespiratória e o mesmo intervalo de tempo de administração. Porém, torna-se importante determinar se o protocolo que vem sendo seguido em pediatria apresenta repercussões que poderiam ou não ser as mais adequadas ao paciente.

OBJETIVO

Avaliar a eficácia de diferentes doses, tempos para infusão da primeira dose, intervalos de administração de doses subsequentes, e número de doses de epinefrina na sobrevida de crianças e adolescentes que sofreram parada cardiorrespiratória extra e intra-hospitalar.

MÉTODOS

Realizou-se revisão sistemática de literatura, por meio de artigos da base de dados PubMedⓇ/MEDLINEⓇ. Utilizaram-se os descritores “ cardiac arrest ”, “ children ” e “ epinephrine ”, combinados com o operador booleano “ AND ”.

Em seguida, utilizaram-se quatro filtros do PubMedⓇ: período (Data de publicação: 01/01/2000 até 10/02/2019), estudos em humanos ( Humans ), artigos nos idiomas inglês, português e espanhol ( English, Portuguese, Spanish ) e faixa etária de zero a 18 anos ( Child: birth-18 years ). Os artigos selecionados tiveram título e resumo avaliados. Foram incluídos os estudos que avaliaram a eficácia da epinefrina no tratamento da parada cardiorrespiratória pediátrica.

RESULTADOS

Foram encontrados 222 artigos e, destes, 126 foram excluídos na análise inicial devido aos quatro filtros do PubMedⓇ: 89 estudos publicados antes de 1° de janeiro de 2000; 14 estudos realizados em animais; 14 estudos com idiomas diferentes do inglês, espanhol e português; 9 estudos realizados em pacientes com idade acima de 18 anos.

Os 96 artigos restantes foram avaliados. Destes, 95 estavam no idioma inglês e um em espanhol. Foram excluídos 80 artigos, pois não descreveram a eficácia da epinefrina no tratamento da parada cardiorrespiratória pediátrica em relação à sobrevida ( Figura 1 ).

Figura 1. Fluxograma do estudo.

Figura 1

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Na segunda etapa, foram excluídos 8 revisões de literatura, 6 relatos de caso, 3 cartas ao editor, 57 estudos que não avaliaram especificamente epinefrina na parada cardiorrespiratória pediátrica e 6 por outros motivos.

Foram selecionados 16 estudos5 , 13 - 27encontrados na base de dados PubMedⓇ/MEDLINEⓇ( Tabela 1 ). Embora não tenha sido realizada busca de artigos em outras bases de dados, todos estavam citados na base de dados Scopus e 15 estavam na base ISI Web of Science . Apenas o periódico Anales de Pediatría 27não estava presente na base de dados ISI Web of Science . Dois estudos eram ensaios clínicos aleatorizados e 14 eram observacionais.

Tabela 1. Estudos selecionados para a revisão.

Referência Tipo de estudo Tipo de parada cardiorrespiratória Número de eventos Objetivo Conclusão
Fukuda et al.(5) Observacional Extra-hospitalar 225 Avaliar tempo para primeira epinefrina e sobrevida Quanto menor o tempo para a primeira epinefrina, maior a sobrevida
Andersen et al.(13) Observacional Intra-hospitalar 1.558 Avaliar tempo para primeira epinefrina com sobrevida e prognóstico neurológico Quanto menor o tempo para a primeira epinefrina, maior a sobrevida e melhor o prognóstico neurológico
Lin et al.(14) Observacional Traumática extra-hospitalar 388 Avaliar tempo para primeira epinefrina com sobrevida e prognóstico neurológico O tratamento precoce com epinefrina pode não proporcionar benefícios em casos traumáticos
Hoyme et al.(15) Observacional Intra-hospitalar 1.630 Avaliar diferentes intervalos entre doses de epinefrina e sobrevida Intervalos de administração maiores que os recomendados atualmente apresentam maior sobrevida
Meert et al.(16) Observacional Extra-hospitalar 295 Avaliar a conduta durante a parada cardiorrespiratória com sobrevida e prognóstico neurológico Quanto maior o número de doses de epinefrina, menor a sobrevida e pior o prognóstico neurológico
Moler et al.(17) Observacional Extra-hospitalar 138 Avaliar diferentes condutas no tratamento da parada cardiorrespiratória e sobrevida Quanto maior o número de doses de epinefrina, menor a sobrevida
de Mos et al.(18) Observacional Intra-hospitalar 91 Avaliar diferentes condutas no tratamento da parada cardiorrespiratória e sobrevida Quanto maior o número de doses de epinefrina, menor a sobrevida
Young et al.(19) Observacional Extra-hospitalar 601 Descrever as características epidemiológicas, as taxas de sobrevivência e os desfechos neurológicos Quanto maior o número de doses de epinefrina, menor a sobrevida e pior o prognóstico neurológico
Checchia et al.(20) Observacional Extra-hospitalar 24 Determinar se a medida da troponina I cardíaca em crianças com parada cardiorrespiratória fora do hospital prevê a gravidade da lesão miocárdica Quanto maior o número de doses de epinefrina, menor a sobrevida
Donoghue et al.(21) Observacional Não traumática intra-hospitalar 16.834 (16.245 adultos e 537 crianças) Comparar os resultados da ressuscitação cardiopulmonar para pacientes pediátricos e adultos e identificar fatores associados às diferenças nos resultados entre crianças e adultos Utilizou-se mais epinefrina em crianças Na análise multivariada, a idade não teve associação na sobrevida
Enright et al.(22) Observacional Extra-hospitalar durante exercício físico 9 Determinar se a sobrevivência a longo prazo é influenciada por intervenções específicas de ressuscitação Crianças que sofrem parada cardiorrespiratória durante exercício físico apresentam principalmente ritmos desfibriláveis e a epinefrina, nessa situação, pode ser maléfica
Tibballs et al.(23) Observacional Intra-hospitalar 111 Avaliar o impacto de diferentes fatores no prognóstico da parada cardiorrespiratória em crianças Doses de epinefrina superiores a 0,015mg/kg apresentam menor sobrevida
Perondi et al.(24) Aleatorizado Intra-hospitalar 68 Comparar a eficácia entre a dose padrão e dose alta de epinefrina em parada cardiorrespiratória pediátrica hospitalar Os dados sugerem que a terapia com doses elevadas pode ser pior do que a terapia de dose padrão
Guay et al.(25) Observacional Intra-hospitalar 203 Avaliar a eficácia das intervenções avançadas de suporte de vida na parada cardiorrespiratória pediátrica Para a epinefrina administrada por via intravenosa, a dose padrão de 0,01mg/kg parece apropriada como a primeira dose
Patterson et al.(26) Aleatorizado Extra-hospitalar 230 Avaliar se a dose elevada de epinefrina utilizada durante a parada cardiorrespiratória extra-hospitalar refratária às intervenções pré-hospitalares melhora o retorno da circulação espontânea, a sobrevida e o prognóstico neurológico A dose alta de epinefrina não melhora e nem diminui o retorno da circulação espontânea, a sobrevida e o prognóstico neurológico em comparação com dose padrão na parada cardiorrespiratória extra-hospitalar
Rodríguez Núñez et al.(27) Observacional Intra e extra-hospitalar 92 Avaliar o impacto na sobrevida de epinefrina (intravenosa ou intraóssea) em dose elevada em comparação com dose padrão em crianças com parada cardiorrespiratória Não houve diferença nos dois grupos em relação ao retorno da circulação espontânea, tempo de ressuscitação total, estado neurológico no final do episódio e sobrevivência à alta hospitalar e em 1 ano de acompanhamento
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DISCUSSÃO

Considerando-se os artigos encontrados na literatura a partir dos descritores escolhidos, os aspectos relevantes a serem comparados são os seguintes.

Tempo para administração da primeira epinefrina

Três estudos avaliaram se o tempo para a administração da primeira epinefrina influenciava na sobrevida.

Fukuda et al., analisaram 225 crianças entre 1 e 17 anos que sofreram parada cardiorrespiratória extra-hospitalar no Japão, por meio de levantamento retrospectivo. Houve relação direta entre o menor tempo para administração da epinefrina e maior sobrevida em 30 dias (p<0,0001).5

Andersen et al., avaliaram 1.558 crianças menores de 18 anos, que sofreram parada cardiorrespiratória intra-hospitalar nos Estados Unidos, por meio de um coorte retrospectivo. Assim como o estudo anterior, também houve relação entre menor tempo da administração com maior sobrevida (p<0,001).13Este estudo também relatou que o prognóstico neurológico foi melhor no grupo com menor tempo de administração.13Entretanto, Lin et al., verificaram que o tempo para a primeira dose de epinefrina não influenciou na sobrevida e nem no prognóstico neurológico, ao estudarem 388 crianças menores de 18 anos atendidas em 3 centros de emergências de Taiwan (p=0,234).14

Os diferentes estudos que avaliaram o tempo para a administração da primeira epinefrina foram realizados com número expressivo de crianças, porém com idades que podem ter variado desde bebês até 18 anos. O estudo de Fukuda et al.,5apresentou predomínio de adolescentes acima de 12 anos (76,9%). O estudo de Andersen et al.,13era constituído por uma amostra de crianças com mediana de 9 meses de idade. Lin et al.,14apresentaram 63,4% de crianças e adolescentes com idades superiores a 10 anos. Apesar da dispersão da faixa etária nos diferentes estudos, este fator não parece ter sido determinante nas diferenças observadas no estudo de Lin et al.,14comparado aos de Fukuda et al.,5e Andersen et al.13Portanto, o fator que pode justificar este resultado conflitante é o fato de o estudo de Lin et al.,14avaliar somente parada cardiorrespiratória extra-hospitalar secundária ao trauma, enquanto os outros dois estudos avaliaram todas as causas de parada cardiorrespiratória.

Estudo realizado com 35.065 adultos que sofreram parada cardiorrespiratória extra-hospitalar não traumática demonstrou que quando o Suporte Avançado de Vida (epinefrina, obtenção de vias aéreas e desfibrilação manual) era aplicado precocemente, havia aumento na sobrevida da vítima, quando comparado ao atendimento somente com Suporte Básico de Vida (ressuscitação cardiopulmonar e desfibrilador externo automático).28

Intervalo de tempo entre as doses de epinefrina

Uma revisão retrospectiva do registro da AHA Get With The Guidelines Ⓡ -Resuscitation , com 1.630 crianças menores de 18 anos que sofreram parada cardiorrespiratória intra-hospitalar, evidenciou que intervalos entre as doses de epinefrina maiores (>5 a <8 minutos, e 8 a <10 minutos) que as recomendadas atualmente pela AHA apresentam melhores resultados de sobrevida à alta hospitalar.15Estudo realizado em 2014 na população adulta encontrou resultados semelhantes após avaliar 20.909 parada cardiorrespiratória intra-hospitalares.29

Embora se trata de um achado importante com número amostral elevado, este é o único estudo na literatura que evidencia achados distintos daqueles preconizados até o momento.

Número de doses de epinefrina administrada

Sete estudos encontraram relação inversa entre número de doses de epinefrina e sobrevida.

Foi realizada análise secundária de dados do Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital Trial , de 36 unidades de terapia intensiva (UTI) pediátricas no Canadá e Estados Unidos, com 295 crianças maiores de 48 horas de vida e menores de 18 anos que sofreram parada cardiorrespiratória extra-hospitalar. Este estudo evidenciou 80% de sobrevida quando a epinefrina não precisou ser administrada, 54% com uma dose, 41% com duas doses, 38% com três doses, 36% com quatro doses, 11% com cinco ou mais doses.16Este estudo encontrou a mesma relação entre o número de doses e o prognóstico neurológico definido pela segunda edição da Vineland Adaptive Behavior Scales (VABS-II).16

Coorte retrospectiva, com 138 crianças maiores de 24 horas de vida e menores de 18 anos, de 15 hospitais, vítimas de parada cardiorrespiratória extra-hospitalar, demonstrou que o número de doses de epinefrina foi inversamente associado à alta hospitalar (p<0,01).17Entre os 46 pacientes que receberam mais que três doses de epinefrina, apenas sete sobreviveram.17O número máximo de doses de adrenalina recebidas em um sobrevivente normal foi cinco.17

Estudo retrospectivo com 91 crianças menores de 18 anos que sofreram parada cardiorrespiratória em UTI pediátrica verificou que a sobrevida das crianças que receberam de duas a três doses foi de 48%, enquanto as que receberam quatro ou mais doses foi de 13%.18

Análise secundária de dados de um estudo prospectivo realizado de 1994 a 1997 avaliou 601 parada cardiorrespiratória extra-hospitalares de crianças menores de 12 anos em duas cidades da Califórnia.19Crianças que receberam mais de três doses de epinefrina ou mais de 31 minutos de ressuscitação cardiopulmonar não sobreviveram.19

Estudo prospectivo observacional com 24 crianças hospitalizadas na UTI pediátrica e que sofreram parada cardiorrespiratória extra-hospitalar, com idades entre 8 meses e 17 anos, concluiu que os sobreviventes receberam 1,3 +/- 2,2 doses de epinefrina em comparação com 2,9 +/- 1,6 doses para não sobreviventes (p=0,02).20

Uma coorte retrospectiva com 10 anos de duração avaliou 16.834 parada cardiorrespiratória (537 em crianças) não traumáticas atendidas em departamento de emergência.21A mediana das doses de epinefrina foi de 3 (zero a 15) em crianças e 2 (zero a 9) em adultos (p<0,001).21Os adultos tiveram retorno mais frequente da circulação espontânea (53% versus 47%; p=0,02), sobrevida em 24 horas (35% versus 30%; p=0,02) e sobrevida para alta (23% versus 20%; p=NS); porém, na análise multivariada, a idade não teve associação com os desfechos.21

Uma hipótese que pode explicar a menor sobrevida com o aumento do número de doses de epinefrina é que, quanto maior o tempo de parada cardiorrespiratória, mais doses serão administradas. Desta forma, a menor sobrevida pode estar relacionada ao tempo de duração da parada cardiorrespiratória e não necessariamente a um efeito adverso da droga. Outro fator que também pode contribuir com a sobrevida de crianças vítimas de parada cardiorrespiratória é o ritmo cardíaco. Crianças que apresentam inicialmente ritmo chocável de parada cardiorrespiratória apresentam maior sobrevida.30Estudo observacional prospectivo realizado em Sidney observou nove crianças menores de 16 anos que sofreram parada cardiorrespiratória extra-hospitalar durante atividade física.22Os seis sobreviventes tiveram parada cardiorrespiratória por ritmo chocável e cinco destes não receberam epinefrina. Os três que faleceram tiveram parada cardiorrespiratória por ritmo não chocável.22Apesar dos achados deste estudo, o número de crianças avaliadas é muito limitado, o que inviabiliza a avaliação estatística adequada que permita chegar a conclusões que se reflitam em termos populacionais.

Dosagem da epinefrina administrada

Foram encontrados cinco estudos que avaliaram a relação entre dose da epinefrina administrada e sobrevida. Três concluíram que a dose padrão (0,01mg/kg) apresenta melhores resultados. Dois concluíram que a dose padrão ou doses superiores apresentam o mesmo desfecho de sobrevida. Nenhum estudo demonstrou melhora na sobrevida com superdosagens de epinefrina.

Estudo prospectivo com 111 crianças concluiu que doses superiores a 0,015mg/kg administradas para ritmos não chocáveis podem causar fibrilação ventricular secundária, que tem desfecho pior do que a fibrilação ventricular primária.23

Estudo prospectivo, randomizado, duplo-cego, comparou doses elevadas de epinefrina (0,1mg/kg) com epinefrina de dose padrão como terapia de resgate para parada cardiorrespiratória hospitalar em crianças após falha de uma dose inicial padrão (n=68).24Os dois grupos de tratamento não diferiram significativamente em termos de taxa de retorno da circulação espontânea (que ocorreu em 20 pacientes no grupo de doses elevadas, e em 21 do grupo de dose padrão).24Contudo, a taxa de sobrevivência em 24 horas foi menor no grupo de dose elevada de epinefrina como terapia de resgate quando comparada ao grupo de dose padrão.24Um dos 34 pacientes do grupo com altas doses sobreviveu durante 24 horas, em comparação com 7 dos 34 pacientes no grupo de dose padrão (p=0,05).24

Estudo retrospectivo comparou dose padrão, doses baixas e doses altas de epinefrina na parada cardiorrespiratória pediátrica. Não houve sobrevida imediata ou após 24 horas no grupo que recebeu dose inferior a 0,0018mg/kg.25No grupo que recebeu doses acima da padrão, não houve sobrevida imediata em crianças que receberam mais de 0,0357mg/kg, e nem houve sobrevida em 24 horas em crianças que receberam dose superior a 0,019mg/kg.25

Estudo controlado randomizado multicêntrico conduzido em sete hospitais com 230 pacientes menores de 22 anos comparou dose padrão (n=86) com dose dez vezes maior de epinefrina (n=127).26Não houve diferença estatística significativa entre os dois grupos quantos ao desfecho (retorno da circulação espontânea, sobrevida em 24 horas, sobrevida à alta e prognóstico neurológico).26

Estudo prospectivo multicêntrico separou 92 crianças entre 7 dias de vida e 17 anos vítimas de parada cardiorrespiratória em dois grupos.27O primeiro grupo (n=12) recebeu doses padrão de epinefrina enquanto o segundo (n=80) recebia a primeira dose padrão e as demais dez vezes maior.27Não houve diferença nos dois grupos em relação ao retorno da circulação espontânea, ao tempo de ressuscitação total, ao estado neurológico no final do episódio e à sobrevivência à alta hospitalar e em 1 ano de acompanhamento.27Os estudos avaliados nesta revisão mostram que não há vantagens em modificar a dose padrão preconizada pela AHA.

CONCLUSÃO

Há poucos artigos publicados que avaliam o uso da epinefrina na pediatria. Após avaliar os estudos desta revisão, concluímos que a epinefrina deve ser administrada na parada cardiorrespiratória em crianças o mais rápido possível. A dose deve ser a padrão (0,01mg/kg). Apesar dos estudos demonstrarem menor sobrevida com o aumento das doses de epinefrina, esse fato pode ser explicado por outros motivos, como o tempo de ressuscitação cardiopulmonar e o ritmo inicial de parada cardiorrespiratória. Apenas um estudo avaliou o intervalo entre as doses de epinefrina e concluiu que o intervalo recomendado atualmente (3 a 5 minutos) apresenta menor sobrevida quando comparado a intervalos maiores, assim como já demonstrado em adultos, sugerindo que menos epinefrina (dose cumulativa ou frequência) pode ser benéfico na parada cardiorrespiratória pediátrica intra-hospitalar.

Mais estudos precisam ser realizados para um melhor entendimento do ajuste de intervalo e o número máximo de doses de epinefrina − preferencialmente ensaios clínicos aleatorizados.

Articles from Einstein are provided here courtesy of Instituto de Ensino e Pesquisa Albert Einstein

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