The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients: a pilot study.
ABSTRACT Several studies have disclosed the importance of serum adrenocorticotropic hormone and cortisol levels in resuscitation. The objective of this study was to observe the effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest (OHCA) patients.
Prospective, nonrandomized, open-labeled clinical trial.
Emergency department (ED) of National Taiwan University Hospital.
Ninety-seven nontraumatic adult OHCA victims.
Serum adrenocorticotropic hormone and total cortisol levels were examined in all patients. The hydrocortisone group (n = 36) received 100 mg intravenous hydrocortisone during resuscitation, and the nonhydrocortisone group (n = 61) received 0.9% saline as placebo.
Comparison of return of the spontaneous circulation (ROSC) rates between the 2 groups was analyzed. The hydrocortisone group had a significantly higher ROSC rate than the nonhydrocortisone group (61% vs 39%, P = .038). Hydrocortisone administration within 6 minutes after ED arrival led to an increased ROSC rate (90% vs 50%, P = .045). The hydrocortisone and nonhydrocortisone groups did not differ in the development of electrolyte disturbances, gastrointestinal tract bleeding, or infection during early postresuscitation period (gastrointestinal bleeding: 41% vs 46%, P = .89; infection: 50% vs 75%, P = .335). There was no significant difference between the hydrocortisone and nonhydrocortisone groups in terms of 1- and 7-day survival and hospital discharge rates.
Hydrocortisone treatment during resuscitation, particularly when administrated within 6 minutes of ED arrival, may be associated with an improved ROSC rate in OHCA patients.
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ABSTRACT: The plasma catecholamine and serum cortisol responses to cardiac arrest (ventricular fibrillation), cardiopulmonary resuscitation (CPR), and ventricular defibrillation were examined in 10 intact (sham-operated controls) and 10 bilaterally adrenalectomized dogs. One hour after surgery, the cardiac ventricles were electrically fibrillated, and 30 s later Standard American Heart Association CPR was begun. After 12 min of CPR, the ventricles were defibrillated. Cardiac arrest per se results in a massive increase in plasma epinephrine and norepinephrine concentrations and indicates that the adrenal medullas are the predominant source of this response. Although the epinephrine response was virtually nonexistent in the adrenalectomized dogs, the norepinephrine response was approximately 30% of that in the sham-operated control animals. Thus there is an adrenomedullary, and perhaps a sympathetic neural, component to the sympathochromaffin response to cardiac arrest. Resuscitation from experimental cardiac arrest tended (P greater than 0.05 less than 0.1) to be lower in the adrenalectomized dogs (1 of 10) than in the animals with intact adrenal glands (6 of 10).The American journal of physiology 10/1987; 253(3 Pt 1):E283-9.
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ABSTRACT: To assess whether plasma endothelin, adrenaline, noradrenaline, arginine vasopressin, adrenocorticotropin, and cortisol concentrations were higher during cardiopulmonary resuscitation in patients in whom resuscitation was successful than in those in whom it failed, and to measure the concentrations of these hormones in the immediate post-resuscitation phase. Prospective, descriptive study. Emergency medical service at a university hospital. 60 patients with cardiac arrest out of hospital. Blood samples were drawn and blood pressure and heart rate were measured during cardiopulmonary resuscitation, before and after the first dose of adrenaline was given and at 5, 15, 30, and 60 minutes after the restoration of spontaneous circulation. Plasma hormone concentrations were measured by radio-immunoassays. 24 of the 60 patients were successfully resuscitated and admitted to hospital: 36 were not. During cardiopulmonary resuscitation before adrenaline was given, the plasma concentration of endothelin (mean (SEM)) in resuscitated and in not resuscitated patients was 4.3 (0.9) pg/ml and 5.5 (0.4) pg/ml respectively (NS), adrenaline was 14.1 (2.0) ng/ml and 25.3 (3.6) ng/ml (P < 0.01), noradrenaline was 5.0 (0.9 ng/ml) and 8.4 (1.1 ng/ml) (P < 0.05), arginine vasopressin was 193 (28) pg/ml and 70 (9) pg/ml (P < 0.001), adrenocorticotropin was 128 (34) pg/ml and 57 (6) pg/ml (P < 0.05), and cortisol was 18 (3) microgram/dl and 15 (2) microgram/dl (NS). During cardiopulmonary resuscitation after adrenaline was given endothelin in resuscitated and in not resuscitated patients was 4.0 (1.0) pg/ml and 5.3 (0.5) pg/ml (NS), adrenaline was 145 (16) ng/ml and 201 (21) ng/ml (P < 0.05), noradrenaline was 3.9 (0.9) ng/ml and 8.3 (1.1) ng/ml (P < 0.01), arginine vasopressin was 177 (27) pg/ml and 58 (9) pg/ml (P < 0.001), adrenocorticotropin was 234 (92) pg/ml and 85 (9) pg/ml (P < 0.001), and cortisol was 17 (2) microgram/dl and 13 (2) microgram/dl (NS). Despite a tremendous adrenosympathetic response, the lower arginine vasopressin and adrenocorticotropin concentrations during cardiopulmonary resuscitation in patients in whom resuscitation failed may influence vital organ perfusion and hence the success of resuscitation. Plasma concentrations of arginine vasopressin and adrenocorticotropin may have a more important effect on outcome than previously thought.Heart (British Cardiac Society) 02/1996; 75(2):145-50. · 5.01 Impact Factor
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ABSTRACT: To analyze the relationship between stress hormones (arginine vasopressin (ADH), adrenocorticotropic hormone (ACTH) and cortisol and the outcome of patients resuscitated after cardiopulmonary arrest (CPA). Thirty-six patients were enrolled in this study. In 36 of the resuscitated cases, 27 were non-survivors and 9 survived. The survival group was defined as cases either in a persistent vegetative state, with some disability or good recovery 1 month after return of spontaneous circulation (ROSC). The non-survival group was defined as cases who died within 1 month. The plasma ADH and ACTH levels and the serum cortisol levels in both the surviving and the non-surviving patients were 82.3+/-74.5 and 149.6+/-135.4 (pg/ml), 239.7+/-327.4 and 282.4+/-553.0 (pg/ml), 34.1+/-11.2 and 19.0+/-12.8 (g/ml) (mean+/-S.D., respectively). The plasma ADH and ACTH levels showed no significant difference between the two groups. The serum cortisol levels were significantly higher in survivors than in the non-survivors (P=0.029). We also used the receiving-operating characteristics (ROC) curves to evaluate the optimal cutoff value of the concentration of serum cortisol as a predictive maker of non-surviving patients. The cutoff value of 16.7 g/ml for the concentrations of serum cortisol was a 1.00 positive predictive value and a 1.00 specificity at a 0.519 negative predictive and a 0.409 sensitivity for predicting non-surviving patients. The area under the ROC curve was calculated to be 0.858 at a prevalence of 0.58. The plasma ADH levels correlated significantly and positively with the plasma ACTH levels (r=0.516, P<0.0010). We concluded that the serum cortisol levels were significantly higher in survivors than in non-survivors resuscitated after CPA.Resuscitation 08/2004; 62(1):55-60. · 4.10 Impact Factor
The effect of hydrocortisone on the outcome of
out-of-hospital cardiac arrest patients: a pilot study
Min-Shan Tsai MD, Chien-Hua Huang MD, Wei-Tien Chang MD,
Wen-Jone Chen MD, PhD*, Chiung-Yuan Hsu MD, Cheng-Chun Hsieh MD,
Chih-Wei Yang MD, Wen-Chu Chiang MD,
Matthew Huei-Ming Ma MD, PhD, Shyr-Chyr Chen MD
Department of Emergency Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan
Received 25 September 2006; received in revised form 12 December 2006; accepted 13 December 2006
Objective: Several studies have disclosed the importance of serum adrenocorticotropic hormone and
cortisol levels in resuscitation. The objective of this study was to observe the effect of hydrocortisone on
the outcome of out-of-hospital cardiac arrest (OHCA) patients.
Design: Prospective, nonrandomized, open-labeled clinical trial.
Setting: Emergency department (ED) of National Taiwan University Hospital.
Patients and Participants: Ninety-seven nontraumatic adult OHCA victims.
Interventions: Serum adrenocorticotropic hormone and total cortisol levels were examined in all
patients. The hydrocortisone group (n = 36) received 100 mg intravenous hydrocortisone during
resuscitation, and the nonhydrocortisone group (n = 61) received 0.9% saline as placebo.
Measurements and Results: Comparison of return of the spontaneous circulation (ROSC) rates between
the 2 groups was analyzed. The hydrocortisone group had a significantly higher ROSC rate than the
nonhydrocortisone group (61% vs 39%, P = .038). Hydrocortisone administration within 6 minutes after
ED arrival led to an increased ROSC rate (90% vs 50%, P = .045). The hydrocortisone and
nonhydrocortisone groups did not differ in the development of electrolyte disturbances, gastrointestinal
tract bleeding, or infection during early postresuscitation period (gastrointestinal bleeding: 41% vs 46%,
P =.89;infection:50%vs75%,P =.335).Therewasnosignificantdifferencebetweenthehydrocortisone
and nonhydrocortisone groups in terms of 1- and 7-day survival and hospital discharge rates.
Conclusions: Hydrocortisone treatment during resuscitation, particularly when administrated within
6 minutes of ED arrival, may be associated with an improved ROSC rate in OHCA patients.
D 2007 Elsevier Inc. All rights reserved.
The resuscitation of patients with cardiac arrest has
remained challenging despite efforts in the past decades.
Much effort has been invested in improving the success rate
for the return of spontaneous circulation (ROSC) and
0735-6757/$ – see front matter D 2007 Elsevier Inc. All rights reserved.
This study was supported in part by a grant form the National Taiwan
University Hospital (NTUH 94S161), Taipei, Taiwan.
* Corresponding author. Tel.: +886 2 23562831; fax: +886 2
E-mail address: firstname.lastname@example.org (W.-J. Chen).
American Journal of Emergency Medicine (2007) 25, 318–325
outcomes in these patients. Several research efforts, based on
animal and human studies, have disclosed the importance of
the hypothalamic-pituitary-adrenal axis in resuscitation [1-8].
Successfully resuscitated patients were reported to have
increasedserum adrenocorticotropic hormone(ACTH)levels
compared to nonresuscitated patients [2,3,6]. Low serum
with early postresuscitation mortality [2,4,5]. These findings
have raised questions concerning the relationship between
cardiac arrest and adrenal function. Cardiac arrest has been
documented to impair cortisol release from the adrenal cortex
. Frequent relative adrenal insufficiency in postresuscita-
tion survivors may reflect cortisol levels that are insufficient
in cases of extreme stress, as seen in patients with cardiac
arrest [2,9]. Therefore, we hypothesized that a high probabil-
ity of cardiac arrest patients may encounter adrenal insuf-
ficiency during resuscitation, which results from either pre-
existed undiscovered adrenal insufficiency or cardiac arrest–
induced adrenal dysfunction. Corticosteroid supplements
during resuscitation significantly increased ROSC rates in an
animal study . To the best of our knowledge, there has not
beenanyresearchperformed on humansaddressingtheeffect
of corticosteroid use in cardiac arrests. The objective of this
prospective clinical trial is to evaluate the effect of hydrocor-
tisone administration during resuscitation on the outcomes in
out-of-hospital cardiac arrest (OHCA) patients.
2. Materials and methods
This prospective, nonrandomized, open-labeled clinical
trial, approved by the institutional review board, enrolled
OHCA victims from the emergency department (ED) of the
National Taiwan University Hospital from October 2004 to
The university hospital, suited in the downtown area of
Taipei City, is a tertiary-referred center hospital with about
100000 ED visits per year [10,11]. The emergency medical
service configuration is a fire-based, single-tiered, basic-
life-support and defibrillation system staffed by emergency
medical technicians (EMTs) who have completed at least
264 hours of paramedic training. EMTs can perform
laryngeal mask airway and tracheal intubation, and admin-
ister intravenous epinephrine. At least 2 EMTs, equipped
with an automated external defibrillator (AED), attend each
call. The median call-to-response time is about 4 minutes in
OHCA patients, and the median call-to-shock time by AED
is about 9 minutes in patients with ventricular tachycardia
and fibrillation [12,13].
2.2. Selection of participants
Eligible patients included nontraumatic OHCA patients
older than 18 years. Patients with do-not-attempt-
resuscitation (DNAR) orders, pregnant women, extracorpo-
real membrane oxygenation users during resuscitation,
concurrent steroid users, patients with known adrenal
insufficiency, patients who were successfully resuscitated
before ED arrival or before seeking their willingness to be a
trial participant, and OHCA survivors who were transferred
to other hospitals for intensive care were all excluded from
this clinical trial.
The OHCA patients received cardiopulmonary resusci-
tation (CPR) according to the advanced cardiovascular life
support guidelines established by the American Heart
Association in 2000 . Serum ACTH and total cortisol
levels were examined upon arrival at the ED in all OHCA
patients. The consecutively enrolled patients were divided
into 2 groups, namely, the hydrocortisone group and the
nonhydrocortisone group. The hydrocortisone group in-
Flow diagram of enrolled patients. ECMO, extracorporeal
The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients 319
volved patients the families of whom agreed that the
patient should receive hydrocortisone during resuscitation,
and the nonhydrocortisone group involved patients the
families of whom hesitated or refused to have the patient
receive the drug because of either the absence of a key
person or possible side effects of the hydrocortisone.
Patients in the hydrocortisone group were given 100 mg
intravenous hydrocortisone (SOLU-CORTEF, Pharmacia &
Upjohn Company, Kalamazoo, MI) once an agreement was
obtained. Patients in the nonhydrocortisone group were
given the same volume of intravenous 0.9% saline.
Informed consents had been obtained from the relatives
of the enrolled participants after an investigator explained
the intent, risks, and benefits of the study. Successfully
resuscitated OHCA patients were admitted to the intensive
care unit and received postresuscitation care. Patients
participating in the trial did not receive therapeutic
hypothermia during or after resuscitation.
2.4. Methods of measurement
Blood samples were collected from the femoral vein and
preserved in a prechilled polysterene tube containing EDTA–
in duplicate using a solid-phase chemiluminescent immuno-
metric assay (DPC IMMULITE 2000, Siemens, Berlin,
Germany), with respective sensitivity of 5 pg/mL and
1 Ag/dL. Normal ACTH concentrations range from 10 to
Demographic comparison between hydrocortisone and nonhydrocortisone groups
Age (y) (average)
Coronary artery disease
Chronic obstructive pulmonary disease
End-stage renal disease
Cerebral vascular disease
ACTH (pg/mL) (mean)
High ACTH member (N65 pg/mL)
Total cortisol (lg/dL) (mean)
Normal-to-high cortisol member (N20 lg/dL)
70.4 F 15.5
115.3 F 190.2
43.0 F 49.9
73.8 F 16.6
124.1 F 135.1
36.9 F 24.5
P b .05 was considered statistically significant.
Resuscitation comparison between hydrocortisone and nonhydrocortisone groups
Others (noncardiac and nonrespiratory)
First monitored rhythm
Pulseless electrical activity
Call-to-response time (min)
Prehospital epinephrine use
Prehospital AED shock number
Inhospital epinephrine dosage (mg) (median [range])
Inhospital defibrillation (patient no.)
6.6 F 5.0
0.3 F 0.8
5.6 F 5.4
0.2 F 0.8
P b .05 was considered statistically significant.
M.-S. Tsai et al. 320
65 pg/mL. Normal total cortisol concentrations in the
morning range between 5 and 25 lg/dL.
2.5. Outcome measurements
Resuscitation elements were collected according to the
Utstein style . Causes of OHCA were classified as
cardiac, respiratory, and noncardiac and nonrespiratory
events. Return of the spontaneous circulation was defined
as a palpable pulse with measurable blood pressure, and
sustained ROSC was deemed to have occurred when chest
compressions were not required for 20 consecutive minutes.
In survivors, we collected the presence of postresuscitation
shock and the highest Acute Physiology and Chronic Health
Evaluation (APACHE) II score taken in the first 24 hours
after ROSC, the serum sodium and potassium levels within
24 hours, gastrointestinal (GI) tract bleeding, or infection
within 7 days after ROSC, 1-day and 7-day survival rates,
rate of hospital discharge, the cerebral performance category
(CPC) scale  and Glasgow Coma Scale (GCS) scores
when discharged, and the duration of hospitalization. The
postresuscitation shock was defined as the necessity of
vasopressor tokeep systolic bloodpressuremore than90 mm
Hg.Infections that developed within7 days after ROSC were
described in our previous study . Gastrointestinal tract
bleeding was considered when the guaiac test was positive
for stool samples or for nasogastric tube drainage or when a
definitive diagnosis was made by panendoscopy. The CPC
scale (1 = good performance, 2 = moderate disability, 3 =
severe disability, 4 = coma or vegetative state, and 5 = brain
death) was assessed by primary care physicians.
2.6. Data collection and processing
Supposed that the hydrocortisone administration might
increase the ROSC rate from 30% to 50% with the SD of
10%, the required sample size to achieve an 80% power at
a = .05 for correctly detecting such difference was 31. Data
was saved in a Microsoft Excel database (Microsoft Excel
2002; Microsoft Corporation, Seattle, Wash) and then
analyzed with SPSS software for Windows (Release 10.0;
SPSS, Inc, Chicago, Ill). Mean and SDs were used to
describe approximately normally distributed data. The
Student t test was used for comparison of normally
distributed continuous variables of the 2 groups. Median
and range were used to describe data without normal
distribution. The Mann-Whitney 2-sample rank sum test
was used to compare continuous variables without normal
distribution between the 2 groups. Binomial variables were
analyzed with v2or Fisher exact test. P b. 05 was regarded
as statistically significant. Univariate covariates with a P
value of less than .2 were tested for predicting ROSC
through multivariate logistic regression.
There were 152 OHCA patients in the National Taiwan
University Hospital during the trial period. Nine patients
were missed in the trial period, and 6 patients had DNAR
orders. Among 109 nontraumatic, adult OHCA patients in
the study period, we excluded 5 patients with ROSC before
seeking permission, 2 patients with extracorporeal mem-
brane oxygenation use during resuscitation, 2 patients with
prehospital ROSC, 2 concurrent steroid users, and 1 patient
who was transferred to another hospital after ROSC. In
total, 97 nontraumatic, adult OHCA patients were enrolled
in this clinical trial (Fig. 1).
The mean age of the patients was 72.5 F 16.2 years, and
42 patients (43%) were men. Cardiac events accounted for
one third of OHCA causes (n = 31, 32 %), and asystole was
the most common first monitored rhythm (n = 79, 81%) as
Comparison of outcomes between hydrocortisone and nonhydrocortisone groups
Hydrocortisone (n = 36) Nonhydrocortisone (n = 61)
Total CPR duration in survivors (min) (median [range])
APACHE II score in survivors
CPC scale (median [range])
GCS score when discharge (median [range])
36.6 F 6.4
35.8 F 7.0
P b .05 was considered statistically significant.
factors related to the return of spontaneous circulation
Multiple logistic regression analysis for independent
Normal-to-high cortisol level
Coronary artery disease
* P b .05.
The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients321
previous studies in the Asian countries [11,12,17,18].
Seventy-three patients (75%) collapsed with witness, but
only 2 patients with witnessed collapse (4%) received
bystander CPR. Forty-six patients (47%) gained ROSC, 44
(45%) had sustained ROSC, 18 (18%) survived more than
7 days, and only 9 (9.3%) survived to hospital discharge.
There were 36 patients (37%) receiving hydrocortisone
and 61 patients (63%) receiving saline during resuscitation.
There was no significant difference between the hydrocor-
tisone and nonhydrocortisone groups when comparing
demographics and levels of serum ACTH and total cortisol
(Table 1). The causes of OHCA, first monitored rhythm, and
CPR events did not differ in these 2 groups (Table 2). The
hydrocortisone group had more patients gaining ROSC
(61% vs 39%, P = .038) and sustained ROSC (58% vs 38%,
P = .049) than the nonhydrocortisone group. No difference
in CPR duration was noted between the survivors from these
2 groups. The 1- and 7-day survival rates, hospital
discharge, CPC scales, and GCS scores when discharged
also showed no significant difference between these
2 groups (Table 3).
In the nonhydrocortisone group, there was a trend toward
increased serum ACTH and total cortisol levels in patients
with ROSC when compared with those without ROSC
(ACTH: 140.7 F 135.9 pg/mL vs 101.8 F 176.7 pg/mL,
P = .278; total cortisol: 38.7 F 19.2 lg/dL vs. 35.8 F
27.7 lg/dL, P = .696). Random serum total cortisol
concentrations less than 20 lg/dL were usually considered
as an adrenal insufficiency [2,4,19-21]. We defined
74 patients with serum total cortisol levels more than
with serum total cortisol level less than 20 lg/dL as the low
cortisol group. In the univariate analyses for factors relating
ROSC, hydrocortisone, witnessed collapse, inhospital defi-
brillation, the normal-to-high cortisol level, coronary artery
disease, and prehospital intubation were associated with
ROSC. Vasopressin use in our study did not associate with
ROSC (odds ratio [OR], 0.81, P = .665) although several
previous studies have shown the potential benefits of
vasopressin in resuscitation. Hydrocortisone and witnessed
collapse were independent predictors for an increased ROSC
rate after multiple logistic regression analysis (Table 4).
Serum sodium and potassium levels during resuscitation
and within 24 hours after ROSC did not differ in these
2 groups. In addition, these 2 groups did not differ in the
development of GI tract bleeding and infection within 7 days
after ROSC. In addition to 22 pneumonia cases, there were
11 urinary tract infections, 6 bacteremia, 2 vascular catheter-
related infections, 1 intra-abdominal infection, and 1 skin
defect–associated infection within 7 days after ROSC
Patients receiving hydrocortisone showed a trend toward
higher ROSC rate in both the normal-to-high and low
cortisol groups (Table 6). The arrival-to-drug interval was
defined as the duration from ED arrival to the application of
study drugs. The involved patients received study drugs after
Comparison of potential complications between survivors in the hydrocortisone and nonhydrocortisone groups
Patient no. with ROSC
UGI bleeding in 7 d after ROSC
Infection in 7 d after ROSC
Serum sodium (mmol/L) level during resuscitation
Serum sodium (mmol/L) level within 24 h after ROSC
Serum potassium (mmol/L) level during resuscitation
Serum potassium (mmol/L) level within 24 h after ROSC
138.6 F 9.0
139.7 F 11.4
6.2 F 2.4
3.9 F 1.2
138.4 F 11.9
140.6 F 7.8
6.3 F 2.7
3.4 F 0.6
P b .05 was considered statistically significant. UGI, upper gastrointestinal tract.
Comparison of outcomes between patients with and without hydrocortisone in groups with different cortisol levels
Normal-to-high cortisol group (N20 lg/dL)
Total cortisol (lg/dL) (mean)
Low cortisol group (b20 lg/dL)
Total cortisol (lg/dL) (mean)
58.8 F 54.0
46.5 F 21.2
9.7 F 5.0
9.8 F 5.1
P b .05 was considered statistically significant.
M.-S. Tsai et al. 322
variable time delays because of differences in the amount of
time it took for the first-line physicians to obtain a brief
history and the investigators to give an explanation of the
study. Hydrocortisone application within 22 minutes after
collapse showed a higher ROSC rate in patients with
witnessed collapse (P = .013). Within 6 minutes after ED
arrival, patients receiving hydrocortisone had a significantly
higher ROSC rate than those receiving placebo (P = .045).
However, there was no difference in ROSC when the arrival-
to-drug interval was beyond 6 minutes (P = .173) (Fig. 2).
This study evaluated the effect of hydrocortisone during
resuscitation in nontraumatic adult OHCA patients. The
application of hydrocortisone during resuscitation, especial-
ly when administrated within 6 minutes after arrival in the
ED, may be associated with improved ROSC rate. The
incidence of electrolyte disturbances, infection, and GI tract
bleeding in the early phase after ROSC did not increase with
Foley et al  disclosed the importance of the adrenal
gland during resuscitation when they discovered fewer
adrenalectomized dogs were successfully resuscitated than
normal ones. Higher serum ACTH and cortisol levels have
been associated with increased ROSC rates and better
short- and long-term outcomes in resuscitated patients
[2-6]. Serum cortisol levels of less than 30 lg/dL were
associated with increased 6- and 24-hour mortality rates
. Besides, OHCA survivors who died of early refractory
shock had lower baseline cortisol levels than those who
later died of neurologic dysfunction . In the non-
hydrocortisone group, we also observed a trend toward
higher serum ACTH and total cortisol levels in successfully
resuscitated patients. These findings raised our interest
about the relationship between the hypothalamic-pituitary-
adrenal axis and cardiac arrest.
Lindner et al  noted that the interval from collapse to
the start of CPR was negatively correlated with serum
cortisol concentrations during resuscitation, thus implying
an impaired cortisol release with cardiac arrest. Vasopressin-
treated pigs had better ROSC rates and higher serum ACTH
and cortisol concentrations than epinephrine-treated ones.
Vasopressin-mediated ACTH, then cortisol release, was
postulated to contribute to the improved outcome . Rats
receiving 0.25 mg hydrocortisone were also reported to
have significantly increased ROSC rates than rats receiving
0.05 mg hydrocortisone and placebo . In our study, more
patients in the hydrocortisone group gained ROSC and
sustained ROSC. Besides, both different cortisol level
groups seemed to benefit from hydrocortisone administra-
tion during resuscitation with increasing ROSC (Table 6).
Because cardiac arrest impairs cortisol release and cardiac
arrest is an extreme stress, most patients with cardiac arrest
may be considered as at least relative adrenal dysfunction.
In addition to patients with pre-existed undiscovered adrenal
insufficiency, the administration of hydrocortisone during
resuscitation may improve ROSC rates in cardiac arrest
patients through supplying adequate serum cortisol levels in
light of such extreme stress. These findings not only
correspond to previous published studies but also support
terms of different timings of drug application during resuscitation.
Collapse-to-drug interval indicates duration from collapse to
hydrocortisone application; arrival-to-drug interval, duration from
emergency department arrival to the use of the study drugs.
(A-C) Return of spontaneous circulation comparison in
The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients323
The hypothalamic-pituitary-adrenal axis plays an impor-
tant role in stress response. Adrenocortical dysfunction
results in hypotension and shock. Glucocorticoids modulate
vascular reactivity to angiotensin II and to catecholamines
and decrease production of vasodilators, such as nitric oxide
. Most researches concerning cardiovascular effect of
corticosteroid were based on severe sepsis and septic shock
needs further researches. However, since more and more
studies suggest postresuscitation syndrome as a bsepsis-likeQ
syndrome [24,25], it is conceivable that sepsis and cardiac
arrests may share similar mechanisms of corticosteroid in
Another interesting topic concerning the application of
hydrocortisone during resuscitation was the timing. Neither
human nor animal studies have previously mentioned this
aspect. Hydrocortisone application within 22 minutes after
collapse showed a higher ROSC rate in patients with
witnessed collapse. We also observed a significantly
increased ROSC rate in patients receiving hydrocortisone
within 6 minutes after ED arrival. No increase in electrolyte
disturbances, GI tract bleeding, or infection during the early
postresuscitation period freed us from the fear of increased
complications resulting from hydrocortisone.
There were several limitations to our study. First, unlike
other clinical trials, resuscitation for OHCA patients is
always critical and is a race against time. It is therefore
difficult to conduct a double-blinded, randomized trial for
this type of study because it takes a certain length of time to
explain the blindness and randomization process to potential
trial participants . Randomized controlled trials are
possible in systems where concomitant consent is not
needed. The current study design could potentially suffer
from selection bias. People may question whether informed
consent might have been less likely to be obtained in patients
who received less attention or who were under more critical
conditions. However, patients with DNAR orders, due to a
terminal disease state, were already excluded from the trial.
As shown in Table 1, there was no significant difference in
comorbidities, causes of OHCA, first monitored rhythm, and
CPR events between these 2 groups. The APACHE II score
between the survivors of these 2 groups did not reveal any
difference as well. It is important to note that all the enrolled
patients were in cardiac arrest, the most critical status a
patient can be in. The first-line physicians, in the study, were
independent in treating patients and adhered to advanced
cardiovascular life support guidelines during resuscitation.
The clinically relevant end point (ROSC) also helped in
eliminating observational bias. Secondly, the hydrocortisone
group had less coronary artery disease, defibrillation, and
more vasopressin use during resuscitation. Although no
statistical significance was noted, these demographic varia-
bles approached a trend. However, except coronary artery
disease (OR, 0.51, P = .168), univariate analyses did not
show the confounding effects of vasopressin and defibrilla-
tion on ROSC, and after multiple logistic regression analysis,
coronary artery disease was not associated with ROSC.
Larger-scale studies may be needed to clarify this possible
association. Thirdly, the cortisol level measured in the study
was total cortisol rather than free cortisol. However, recent
studies discovered that free cortisol, not total cortisol, is
associated with adrenal function. Future researches should
measure free cortisol instead of total cortisol. Lastly, as a
pilot study, the sample size in the study may be too small to
address any definitive conclusion. The poor neurologic
outcome in most survivors also limited our analyses on
long-term outcomes, and the optimal dosage and duration of
hydrocortisone during resuscitation and the early postresus-
citation period needs further extensive researches.
In the present study, the administration of hydrocortisone
during resuscitation, particularly within 6 minutes after ED
arrival, may be associated with improved ROSC rate in
OHCA patients. Hydrocortisone use did not increase the
incidence of electrolyte disturbances, GI tract bleeding, or
infection in the early postresuscitation period. The real
effect of hydrocortisone administration during resuscitation
and in the early postresuscitation period deserves more
extensive and well-designed studies for determining the
affected outcomes in cardiac arrest victims.
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The effect of hydrocortisone on the outcome of out-of-hospital cardiac arrest patients325