Steroid in Paediatric Sepsis. Dr Pon Kah Min Hospital Pulau Pinang

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1 Steroid in Paediatric Sepsis Dr Pon Kah Min Hospital Pulau Pinang

2 Contents Importance of steroid in sepsis Literature Review for adult studies Literature Review for paediatric studies Conclusions.

3 Rationale for Steroid Usage in Sepsis Multiple studies suggest changes during sepsis including: hypopituitary adrenal axis glucocorticoid receptor changes cortisol metabolism. Possible rationales for the use of corticosteroids in sepsis are beneficial pharmacologic effect on the cardiovascular system anti-inflammatory properties

4 Anti-inflammatory properties

5 Hemodynamic Effects of Steroid in Sepsis Immediate nongenomic effects decreasing reuptake of norepinephrine augmenting β-adrenergic receptor sensitivity in the heart increasing calcium availability in myocardial and vascular smooth muscle cells leading to increased myocardial contractility and vasoconstriction. Delayed effects (several hours) through its genomic actions inhibition of prostacyclin production and nitric oxide synthetase leading to increased vascular tone stimulation of intercellular adhesion factor from vascular smooth muscle with a resulting decrease in capillary leak increase in the number of β-adrenergic receptors in the heart resulting in increased myocardial contractility Kusum Menon; CCM, April 2018

6 A Prospective Multicenter Study of Adrenal Function in Critically Ill Children Objectives: to determine the prevalence of adrenal insufficiency, risk factors and potential mechanisms for its development, and its association with clinically important outcomes in critically ill children. A prospective, cohort study, 7 tertiary-care, PICU in Canada on patients up to 17 years of age 381 patients Adrenocorticotropic hormone stimulation tests (1 mg) were performed and adrenocorticotropic hormone levels measured in all participants. Canadian Critical Care Trials Group; American Journal Of Respiratory And Critical Care Medicine 2010

7 A Prospective Multicenter Study of Adrenal Function in Critically Ill Children Prevalence of adrenal insufficiency was 30.2% (95% CI, ). Patients with adrenal insufficiency had higher baseline cortisol levels (28.6 mg/dl vs mg/dl, P, 0.001) were significantly older (11.5 yr vs. 2.3 yr, P, 0.001) Adrenal insufficiency was associated with an increased need for catecholamines (P, 0.001) and more fluid boluses (P ). Canadian Critical Care Trials Group; American Journal Of Respiratory And Critical Care Medicine 2010

8 Adrenal Insufficiency In Children In children, a serum cortisol concentration of > 36 μg/dl and a lack in response to ACTH stimulation may predict a failure to respond to exogenous corticosteroid administration Absolute adrenal insufficiency has been defined as a basal serum cortisol concentration of < 7 μg/dl peak serum cortisol of < 18 μg/dl after stimulation. Relative adrenal insufficiency has been proposed as a basal serum cortisol concentration of < μg/dl < 9 after ACTH stimulation free cortisol < 2

9 Absolute Adrenal Insufficiency Patients at risk of inadequate cortisol/aldosterone production due to absolute adrenal insufficiency in the setting of shock include: purpura fulminans and Waterhouse-Friderichsen syndrome, previously received steroid therapies for chronic illness, children with pituitary or adrenal abnormalities. may benefit from stress doses of hydrocortisone (1mg/kg 6hrly) early in the course of their illness, in the presence of sepsis without shock. Davis et al; CCM, 2017

10 American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock Davis et al; CCM 2017

11 Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 We suggest against using IV hydrocortisone to treat septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability. If this is not achievable, we suggest IV hydrocortisone at a dose of 200 mg per day (weak recommendation, low quality of evidence). Society of Critical Care Medicine CCM 2017

12 Usage of Steroid in Pediatric Sepsis Am J Respir Crit Care Med ; 2015

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15 The Effectiveness of Hydrocortisone in the Management of Severe Infections first prospective randomised, double-blind placebo-controlled studies of steroid administration 100 mg of oral hydrocortisone vs placebo as an adjunctive strategy for patients with severe sepsis and septic shock Findings: No significant survival difference between the treatment and control groups Bennett et al; JAMA, 1963

16 Steroids in the treatment of clinical septic shock. combined a prospective trial with a retrospective analysis contrasting two steroid regimens with placebo in adult surgical patients with septic shock Mortality rates of 11.6% and 9.3% for patients treated with methylprednisolone (one or two doses of 30 mg/kg IV) and dexamethasone (one or two doses of 3 mg/kg IV), respectively, vs 38.4% for patients receiving placebo Standard practice in the late 1970s and early 1980s to administer high-dose corticosteroids at the onset of septic shock Schumer ; Ann Surg, 1976

17 Studies in 1980s 4 studies assessing mortality outcome in patients with septic shock None showed any survival benefit with steroids in septic shock. Sprung (1984) Veterans Administration Trial (1987) Bone (1987) Luce (1988) Steroid use in septic shock began to dwindle in the late 1980 s and 1990 s. Supra-physiological doses of steroids were recognised as having no benefit and considered potentially harmful

18 Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock Placebo-controlled, randomized, double-blind, parallel-group trial involving 19 ICU s in French formed the basis for use of exogenous glucocorticoids in septic shock. 300 patients were randomised within 8 hrs of the onset of septic shock receive placebo or hydrocortisone (50 mg intravenously 6hrly) plus fludrocortisone (50 mcg enterally OD) for 7 days Annane et al; JAMA 2002

19 Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock Based upon a high dose (250 mcg) ACTH stimulation test, all patients were classified as: adequate adrenal reserve (maximum increase in serum cortisol of >9 mcg/dl ) or inadequate adrenal reserve (maximum cortisol increase of 9 mcg/dl) Findings: In patients with inadequate adrenal reserve, Hydrocortisone administration was associated with decreased 28-day mortality (53% vs. 63 %) ICU mortality (58% vs. 70%) hospital mortality (61% vs. 72%) shorter duration of vasopressor use

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21 Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock The limitations of this study include: unadjusted P-value for 28 day mortality in the non-responders is % of patients received etomidate (inhibits adrenal corticosteroid synthesis) use of fludrocortisone, a potential confounder timing to antibiotics was delayed, compared to current standards (mean 6hrs in placebo vs. 7.1hrs in steroid group)

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23 CORTICUS study 499 patients with severe sepsis, 52 participating ICUs Hydrocortisone given as 50 mg in 6-hourly boluses for 5 days and then tapered over 6 days vs placebo Under recruited based on the power calculations Actual mortality (~38%) was much lower than estimated mortality used for power calculation (50%) No difference in 28-day mortality in short corticotropin non-responders 39.2% in hydrocortisone group vs. 36.1% in placebo group P=0.69 Sprung et al; NEJM 2008

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26 Corticosteroids for treating sepsis (Cochrane Review) 33 RCTs, 4268 patients with sepsis. 3 trials included children. Corticosteroids were compared with placebo in all except 5 trials, in which they were compared with standard therapy alone. Annane et al; Cochrane Database of Systematic Reviews 2015

27 Corticosteroids for treating sepsis (Cochrane Review) Corticosteroids reduced 28-day mortality; risk ratio (RR) 0.87, 95% CI: 0.76 to 1.00; P value = 0.05) low quality Treatment with a long course of low-dose corticosteroids significantly reduced 28-day mortality (RR 0.87, 95% CI 0.78 to 0.97; P value = 0.01). moderate quality Corticosteroids also reduced mortality rate in intensive care unit (RR 0.82, 95% CI 0.68 to 1.00; P value = 0.04,) at the hospital (RR 0.85, 95% CI 0.73 to 0.98; P value = 0.03). moderate quality Annane et al; Cochrane Database of Systematic Reviews 2015

28 28-day all cause mortality

29 Corticosteroids for treating sepsis (Cochrane Review) Corticosteroids increased the proportion of shock reversal by day 7 (RR 1.31, 95% CI 1.14 to 1.51; P value = ) by day 28 (RR 1.11, 95% CI 1.02 to 1.21; P value = 0.01) Reduced the SOFA score by day 7 (95% CI to -1.03; P value < ) Reduced the survivors length of stay in the intensive care unit (95% CI to ; P value = 0.01) Corticosteroid increased the risk of hyperglycaemia (RR 1.26, 95% CI 1.16 to 1.37; P value < ) hypernatraemia (RR 1.64, 95% CI 1.28 to 2.09; P value < ). No increase in GI bleeding, superinfection or neuromuscular weakness. Annane et al; Cochrane Database of Systematic Reviews 2015

30 Shock Reversal by D7

31 Shock Reversal at D28

32 SOFA Score by D7

33 Length of ICU Stay For Survivors

34 Elucidate any differences between the drugs and their treatment regimens regarding outcomes for corticosteroid use in adult with septic shock. Complete data from 22 studies and partial data from 1 study. No clear evidence that any one corticosteroid or treatment regime is more effective in reducing mortality reducing the incidence of gastrointestinal bleeding superinfection in septic shock. Hydrocortisone delivered as a bolus or as an infusion was more likely than placebo and methylprednisolone to result in shock reversal Gibbison et al. Critical Care (2017)

35 Network meta-analysis results (right) of mortality up to 28 days for the different interventions. ORs <1 favour the first intervention. Gibbison et al. Critical Care (2017)

36 ADRENAL Trial an investigator-initiated, international, double-blind, parallel-group, randomized, controlled trial 3800 patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days primary outcome was death from any cause at 90 days Venkatesh et al; March 2018; NEJM

37 ADRENAL Trial Patients who received hydrocortisone had more rapid resolution of shock a lower incidence of blood transfusion a shorter time to ICU discharge earlier cessation of the initial episode of mechanical ventilation

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39 ADRENAL Trial No significant between-group differences with respect to mortality at 28 days the rate of recurrence of shock the number of days alive and out of the ICU the number of days alive and out of the hospital the recurrence of mechanical ventilation the rate of renal-replacement therapy incidence of new-onset bacteremia or fungemia. CONCLUSIONS Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. Venkatesh et al; March 2018; NEJM

40 Venkatesh et al; March 2018; NEJM

41 Hydrocortisone plus Fludrocortisone for Adults with Septic Shock Multicenter, double-blind, randomized trial, 1241 patients. Evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. Primary outcome was 90-day all-cause mortality. Secondary outcomes included number of days alive and free of vasopressors, mechanical ventilation, or organ failure mortality at intensive care unit (ICU) discharge hospital discharge at day 28 and day 180. Annane et al; NEJM, March 2018

42 Hydrocortisone plus Fludrocortisone for Adults with Septic Shock 90-day mortality was 43.0% in the hydrocortisone-plus-fludrocortisone group 49.1% in the placebo group (P=0.03). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group : at ICU discharge (35.4% vs. 41.0%, P=0.04) hospital discharge (39.0% vs. 45.3%, P=0.02) day 180 (46.6% vs. 52.5%, P=0.04) Hydrocortisone-plus-fludrocortisone group has significantly higher number of vasopressor-free days to day 28 (17 vs. 15 days, P<0.001) number of organ-failure free days (14 vs. 12 days, P=0.003).

43 Annane et al; NEJM, March 2018

44 Hydrocortisone plus Fludrocortisone for Adults with Septic Shock number of ventilator-free days was similar in the two groups rate of serious adverse events did not differ significantly hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. Annane et al; NEJM, March 2018

45 Paediatric Literatures

46 Low-dose Hydrocortisone In Pediatric Septic Shock: An Exploratory Study In A Third World Setting Open label randomized pilot study PICU of a tertiary care paediatric centre in a third world country. 38 children, 2 months-12 yrs of age, with septic shock unresponsive to fluid therapy alone. Intravenous hydrocortisone 5 mg/kg/day in 4 divided doses followed by half the dose for a total duration of 7 days or normal saline for the same duration. Valoor et al; Pediatr Crit Care Med. 2009

47 Low-dose Hydrocortisone In Pediatric Septic Shock: An Exploratory Study In A Third World Setting RESULTS: trend toward earlier reversal of shock (median 49.5 vs. 70 hrs, p = 0.65, Mann-Whitney U test) lower inotropes requirement in the hydrocortisone-treated patients although the difference was not statistically significant. Mortality rate was similar in both groups. Valoor et al; Pediatr Crit Care Med. 2009

48 Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study Retrospective cohort study clinical database derived from the RESOLVE (REsearching severe Sepsis and Organ dysfunction in children: a global perspective, F1K- MC- EVBP) trial of activated protein C for pediatric severe sepsis. 104 pediatric centers in 18 countries Children with severe sepsis (n = 477), requiring both vasoactiveinotropic infusions and mechanical ventilation. 193 children received corticosteroids; 284 did not. Zimmerman et al; PCCM 2011

49 Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study Both groups had similar demographics and disease severity Indications for corticosteroid prescription were therapeutic (89%, mostly shock) and prophylactic (13%). All cause 28-day mortality among children receiving and not receiving corticosteroids was 15.1% and 18.8%, respectively, p = No difference in mean vasoactive-inotropic infusion days (4.5 days vs. 4.3 days, p=0.59). mean ventilator days (8.3 days vs. 7.7 days, p= 0.38.)

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51 Adjunctive corticosteroid therapy in pediatric severe sepsis: Observations from the RESOLVE study Conclusions: Children with severe sepsis who received adjunctive corticosteroid therapy exhibited similar illness severity compared with those who did not. No definitive improvement in outcomes can be attributable to adjunctive corticosteroid therapy Zimmerman et al; PCCM 2011

52 Systematic Review And Meta-analysis On The Effect Of Steroids In Pediatric Shock RCTs on steroid use and clinical outcomes in pediatric shock. 8 articles; 447 children 7 of the 8 trials were published prior to 1996 all trials were conducted in the developing world 6 of 8 trials were in the setting of dengue shock Overall meta-analysis showed no difference in mortality rates between those who did and did not receive steroids (relative risks, [95% CI, ]; p = 0.197). Menon et al; PCCM Jun 2013

53 Menon et al; PCCM Jun 2013

54 Figure 3. A, Effect of steroids on bleeding risk in pediatric shock. B, Effect of steroids on infection risk Menon et al; PCCM Jun 2013

55 Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis Objective: determined associations between corticosteroids and outcomes in children with septic shock who were stratified by initial mortality risk. retrospective analysis of an ongoing, multi-center pediatric septic shock clinical and biological database. Using a validated stratification tool (PERSEVERE), 496 subjects were stratified into three initial mortality risk strata (low, intermediate, and high). Subjects receiving corticosteroids during the initial 7 days of admission (n = 252) were compared to subjects who did not (n = 244). Atkinson et al; PLoS ONE, 2014

56 Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis Subjects who received corticosteroids had greater organ failure burden higher illness severity higher mortality greater requirement for vasoactive medications PERSEVERE-based mortality risk did not differ between the two groups. For the entire cohort, corticosteroids were associated with increased risk of mortality (OR 2.3, 95% CI , p = 0.004) complicated course (OR 1.7, 95% CI , p=0.012). Atkinson et al; PLoS ONE, 2014

57 Corticosteroids and Pediatric Septic Shock Outcomes: A Risk Stratified Analysis Within each PERSEVERE-based stratum, corticosteroid administration was not associated with improved outcomes. Similarly, corticosteroid administration was not associated with improved outcomes among patients with no comorbidities, nor in groups of patients stratified by PRISM. Conclusions: Risk stratified analysis failed to demonstrate any benefit from corticosteroids in this pediatric septic shock cohort Atkinson et al; PLoS ONE, 2014

58 STRIPES Study

59 A RANDOMIZED CONTROLLED TRIAL OF CORTICOSTEROIDS IN PEDIATRIC SEPTIC SHOCK: A PILOT FEASIBILITY STUDY Objective: To determine the feasibility of conducting a randomized controlled trial of corticosteroids in pediatric septic shock. Randomized, double-blind, placebo controlled trial. 7 tertiary level, PICUs in Canada. Children aged newborn to 17 years inclusive with suspected septic shock. Intervention: Administration of intravenous hydrocortisone versus placebo until hemodynamic stability is achieved or for a maximum of 7 days. Menon et al; PCCM 2017

60 A RANDOMIZED CONTROLLED TRIAL OF CORTICOSTEROIDS IN PEDIATRIC SEPTIC SHOCK: A PILOT FEASIBILITY STUDY Intervention initial IV bolus of 2 mg/kg hydrocortisone, followed by 1 mg/kg of hydrocortisone 6hrly until the patient met stability criteria (defined as no increase in their vasoactive infusions and no administration of a fluid bolus) for at least 12 hours. Hydrocortisone dosing was then reduced to 1 mg/kg 8hrly until all vasoactive infusions had been discontinued for at least 12 hours. If following the de-escalation or discontinuation of hydrocortisone, the patient required fluid boluses and/or an increase in their vasoactive infusion(s), hydrocortisone was increased back to 1 mg/kg of hydrocortisone IV q6h until they met stability criteria again. Hydrocortisone was continued for a maximum of 7 days to prevent adrenal suppression. Menon et al; PCCM 2017

61 A RANDOMIZED CONTROLLED TRIAL OF CORTICOSTEROIDS IN PEDIATRIC SEPTIC SHOCK: A PILOT FEASIBILITY STUDY 57 patients were randomized and 49 patients (23 and 26 patients in the hydrocortisone and placebo groups respectively) were included in the final analysis. From screening to first dose of study drug was 3.8 ± 2.6 hours. No statistical significance difference between the two groups on: time on vasopressors days on mechanical ventilation PICU and hospital length of stay rate of adverse events Menon et al; PCCM 2017

62 Menon et al; PCCM 2017

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64 Rochwerg B, et al. BMJ Open 2017

65 Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Objective: addresses the efficacy and safety of corticosteroids in critically ill patients with sepsis. RCT that compared any corticosteroid to placebo or no corticosteroid in critically ill children and adults with sepsis. 42 RCT, 10,194 patients. Rochwerg B, et al; CCM July 2018

66 Forest plot for short-term mortality. Rochwerg B, et al; CCM July 2018

67 Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Based on low certainty, corticosteroids may achieve a small reduction or no reduction in the relative risk of dying in the short-term (28 31 d) (relative risk, 0.93; 95% CI, ; 1.8% absolute risk reduction; 95% CI, 4.1% reduction to 0.8% increase) Small effect on long-term mortality (60 d to 1 yr) based on moderate certainty (relative risk, 0.94; 95% CI, ; 2.2% absolute risk reduction; 95% CI, 4.1% reduction to no effect). Rochwerg B, et al; CCM July 2018

68 Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Small reductions in length of stay in ICU (mean difference, 0.73 d; 95% CI, 1.78 to 0.31) hospital (mean difference, 0.73 d; 95% CI, 2.06 to 0.60) (moderate certainty). Corticosteroids result in higher rates of shock reversal at day 7 (relative risk, 1.26; 95% CI, ) lower Sequential Organ Failure Assessment scores at day 7 (mean difference, 1.39; 95% CI, 1.88 to 0.89) (high certainty). Rochwerg B, et al; CCM July 2018

69 Rochwerg B, et al; CCM July 2018

70 Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Corticosteroids likely increase the risk of hypernatremia (relative risk, 1.64; 95% CI, ) hyperglycemia (relative risk, 1.16; 95% CI, ) (moderate certainty), May increase the risk of neuromuscular weakness (relative risk, 1.21; 95% CI, ) (low certainty), Appear to have no other adverse effects (low or very low certainty). Rochwerg B, et al; CCM July 2018

71 Corticosteroids in Sepsis: An Updated Systematic Review and Meta-Analysis Subgroup analysis did not demonstrate a credible subgroup effect on any of the outcomes of interest (p > 0.05 for all). Conclusions: In critically ill patients with sepsis, corticosteroids possibly result in small reduction in mortality possibly increasing the risk of neuromuscular weakness. Rochwerg B, et al; CCM July 2018

72 Conclusion In large RCTs of adult, steroid in sepsis resulted in small reduction in mortality faster shock reversal lower SOFA scores Shorter ICU and hospital LOS Increased risks of neuromuscular weakness hyperglycaemia hypernatremia

73 Corticosteroids in Pediatric Septic Shock Are Helpful The absence of a large trial alone cannot be used as proof of lack of benefit, and until such a trial has been completed, pediatric intensivists have a decision to make regarding the administration of a cheap, simple, safe, and widely available intervention. Kusum Menon; CCM, April 2018

74 Thank You