Induced hypothermia using large volume, ice

Induced hypothermia using large volume, ice

Resuscitation 56 (2003) 9 /13
www.elsevier.com/locate/resuscitation
Induced hypothermia using large volume, ice-cold intravenous fluid in
comatose survivors of out-of-hospital cardiac arrest:
a preliminary report
Stephen Bernard a,b,, Michael Buist a, Orlando Monteiro a, Karen Smith b
a
b
The Intensive Care Unit, Dandenong Hospital, David St, Dandenong, Victoria 3175, Australia
Department of Epidemiology and Preventive Medicine, Monash University, St Kilda Rd, Prahran 3181, Victoria, Australia
Received 1 July 2002; accepted 26 July 2002
Abstract
Study hypothesis: Recent studies have shown that induced hypothermia for twelve to twenty four hours improves outcome in
patients who are resuscitated from out-of-hospital cardiac arrest. These studies used surface cooling, but this technique provided for
relatively slow decreases in core temperature. Results from animal models suggest that further improvements in outcome may be
possible if hypothermia is induced earlier after resuscitation from cardiac arrest. We hypothesized that a rapid infusion of large
volume (30 ml/kg), ice-cold (4 8C) intravenous fluid would be a safe, rapid and inexpensive technique to induce mild hypothermia in
comatose survivors of out-of-hospital cardiac arrest. Methods: We enrolled 22 patients who were comatose following resuscitation
from out-of-hospital cardiac arrest. After initial evaluation in the Emergency Department (ED), a large volume (30 ml/kg) of icecold (4 8C) lactated Ringers solution was infused intravenously over 30 min. Data on vital signs, arterial blood gas, electrolyte and
hematological was collected immediately before and after the infusion. Results: The rapid infusion of large volume, ice-cold
crystalloid fluid resulted in a significant decrease in median core temperature from 35.5 to 33.8 8C. There were also significant
improvements in mean arterial blood pressure, renal function and acid /base analysis. No patient developed pulmonary odema.
Conclusion: A rapid infusion of large volume, ice-cold crystalloid fluid is an inexpensive and effective method of inducing mild
hypothermia in comatose survivors of out-of-hospital cardiac arrest, and is associated with beneficial haemodynamic, renal and
acid /base effects. Further studies of this technique are warranted.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Cardiac arrest; Induced hypothermia; Intravenous fluid
Resumo
Hipótesis de estudio : Estudios recientes han demostrado la hipotermia inducida por doce a veinticuatro horas mejora el resultado
en pacientes que han sido resucitados de un paro cardı́aco extrahospitalario. Estos estudios usaron enfriamiento superficial, pero
esta técnica produce disminuciones relativamente lentas en la temperatura central. Los resultados en los modelos animales sugieren
que pueden ser posibles mayores mejorı́as en el resultado si la hipotermia es inducida después de la resucitación del paro cardı́aco.
Planteamos la hipótesis que la rápida infusión de grandes volúmenes (30 ml/kg), de fluidos intravenosos helados (4 8C) serı́a una
técnica segura, rápida y poco costosa para inducir hipotermia leve en sobrevivientes comatosos de paro cardı́aco extrahospitalario.
Métodos : Enrolamos 22 pacientes que estaban comatosos después de ser resucitados de un paro cardı́aco extrahospitalario. Después
de la evaluación inicial en el departamento de emergencias (ED), se les infundió en 30 minutos un gran volumen (30 ml/kg) de
solución Ringer lactato helado (4 8C).Se recogieron datos de signos vitales, gases en sangre arterial, electrolitos y hematologı́a
inmediatamente antes y después de la infusión. Resultados : La rápida infusión de grandes volúmenes de fluidos cristaloides helados
produjo la rápida disminución en la temperatura central de 35.5 a 33.8 8C. También se produjeron mejorı́as significativas en la
presión arterial media, función renal y análisis ácido base. Ningún paciente desarrolló edema pulmonar. Conclusión : Una rápida
Corresponding author. Fax: /61-3-9554-8378
E-mail address: [email protected] (S. Bernard).
0300-9572/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 3 0 0 - 9 5 7 2 ( 0 2 ) 0 0 2 7 6 - 9
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S. Bernard et al. / Resuscitation 56 (2003) 9 /13
infusión de grandes volúmenes de fluidos cristaloides helados es un medio rápido y barato para inducir hipotermia leve en los
sobrevivientes comatosos de un paro cardı́aco extrahospitalario, y está asociado con efectos hemodinámicas, renales y ácido base
beneficiosos. Se garantizan estudios ulteriores de esta técnica.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Palavras chave: Paro cardı́aco; Hipotermia inducida; Fluidos intravenosos
Resumen
Hipótesis de estudio : Estudios recientes han demostrado la hipotermia inducida por doce a veinticuatro horas mejora el resultado
en pacientes que han sido resucitados de un paro cardı́aco extrahospitalario. Estos estudios usaron enfriamiento superficial, pero
esta técnica produce disminuciones relativamente lentas en la temperatura central. Los resultados en los modelos animales sugieren
que pueden ser posibles mayores mejorı́as en el resultado si la hipotermia es inducida después de la resucitación del paro cardı́aco.
Planteamos la hipótesis que la rápida infusión de grandes volúmenes (30 ml/kg), de fluidos intravenosos helados (4 8C) serı́a una
técnica segura, rápida y poco costosa para inducir hipotermia leve en sobrevivientes comatosos de paro cardı́aco extrahospitalario.
Métodos : Enrolamos 22 pacientes que estaban comatosos después de ser resucitados de un paro cardı́aco extrahospitalario. Después
de la evaluación inicial en el departamento de emergencias (ED), se les infundió en 30 minutos un gran volumen (30ml/kg) de
solución Ringer lactato helado (4 8C). Se recogieron datos de signos vitales, gases en sangre arterial, electrolitos y hematologı́a
inmediatamente antes y después de la infusión. Resultados : La rápida infusión de grandes volúmenes de fluidos cristaloides helados
produjo la rápida disminución en la temperatura central de 35.5 a 33.8 8C. También se produjeron mejorı́as significativas en la
presión arterial media, función renal y análisis ácido base. Ningún paciente desarrolló edema pulmonar. Conclusión : Una rápida
infusión de grandes volúmenes de fluidos cristaloides helados es un medio rápido y barato para inducir hipotermia leve en los
sobrevivientes comatosos de un paro cardı́aco extrahospitalario, y está asociado con efectos hemodinámicas, renales y ácido base
beneficiosos. Se garantizan estudios ulteriores de esta técnica.
# 2002 Elsevier Science Ireland Ltd. All rights reserved.
Palabras clave: Paro cardı́aco; Hipotermia inducida; Fluidos intravenosos
1. Introduction
Out-of-hospital cardiac arrest is common and associated with a poor prognosis, with less than 3% of
patients surviving to good outcome at hospital discharge
[1]. Patients who are initially successfully resuscitated by
emergency medical services often remain unconscious
because of severe anoxic brain injury [2]. Recently,
clinical trials of induced hypothermia (IH) have shown
improved outcome in comatose survivors of out-ofhospital cardiac arrest [3 /5]. These studies used surface
cooling with ice packs [3,4] or forced cold air cooling [5],
however, these techniques of surface cooling had
significant limitations. Firstly, these are relatively slow
methods of decreasing core temperature, with a 0.9 8C/
h decrease in core temperature using ice packs [3,4] and
0.3 8C/h using forced cold air cooling [4]. Secondly, the
covering of the patient with ice packs or cooling
blankets during resuscitation is inconvenient for medical
and nursing staff. Finally, the use of ice packs or
refrigerated units (for forced air cooling) limit the use
of these techniques to the hospital environment.
Since there is evidence from animal studies that
outcome is improved if cooling is initiated during
resuscitation or immediately after return of spontaneous
circulation [6,7], the development of a technique to
induce hypothermia which is feasible in the out-ofhospital setting may further improve outcome. We
hypothesized that a rapid intravenous infusion of large
volume (30 ml/kg), ice-cold (4 8C) lactated Ringers
solution would be an effective alternative to surface
cooling for the induction of mild hypothermia. We
report our preliminary experience with this technique.
2. Materials and methods
The study was undertaken in the Emergency Department (ED) of Dandenong Hospital in Melbourne,
Victoria, Australia. Patients were eligible for inclusion
in the study if they arrived unconscious at the ED after
resuscitation by paramedics from out-of-hospital cardiac arrest. Exclusion criteria included children (B/18
years), possible pregnancy (femalesB/50 years), coma
possibly due to cerebrovascular accident or head
trauma, cardiogenic shock (systolic blood pressureB/
90 mmHg despite adrenaline (epinephrine) infusion,
clinical signs of pulmonary oedema, patients with a
diagnosed terminal illness and spontaneous hypothermia (B/34 8C at initial measurement).
Date on the time from collapse to ambulance call, call
to ambulance arrival, and ambulance arrival to return of
spontaneous circulation and initial cardiac rhythm was
recorded from the ambulance Patient Care Record.
Routine management in the ED included mechanical
ventilation with 100% oxygen, resuscitation of the
circulation and maintenance of a mean arterial blood
pressure of 90 /100 mmHg using either adrenaline or
S. Bernard et al. / Resuscitation 56 (2003) 9 /13
glyceryl tri-nitrate infusions as required. Following
assessment of neurological status and confirmation of
coma, vecuronium 20 mg was administered intravenously. Midazolam 1/5 mg was also administered
intravenously. Monitoring included continuous electrocardiogram and invasive blood pressure. A central
venous catheter was inserted if thrombolytic therapy
was not indicated. A bladder catheter incorporating a
temperature probe was inserted. Routine investigations
included a 12 lead electrocardiogram, chest X-ray,
electrolyte, haematology, cardiac enzymes, and arterial
blood gas analysis.
Immediately following this initial evaluation and the
drawing of blood for laboratory analysis, an intravenous
infusion of 30 ml/kg lactated Ringers solution was
administered over 30 min via either a peripheral cannula
or femoral venous catheter, using a pressure bag and
standard intravenous infusion equipment. The lactated
Ringers solution was stored at a controlled temperature
(4 8C) in the ED blood refrigerator until required. At
the conclusion of the infusion, vital signs were recorded
and blood sent for arterial blood gas, electrolyte and
haematological analysis. Arterial blood gases were
corrected for temperature. After this data collection,
ice packs were placed on the patient to decrease core
temperature to 33 8C.
Patients were admitted to the Intensive Care Unit
(ICU), where hypothermia at 33 8C was maintained for
12 h, with active re-warming over 6 h, following a
previously described protocol [3,4].
Statistical analysis was undertaken using the commercial statistical package Stata [8]. Differences between
the pre-fluid and post-fluid variables were analyzed
using the Wilcoxon signed-rank test. A value of P B/
0.05 was considered significant.
The study was approved by the Institutional Ethics
Committee. Informed, written consent was obtained
from the next-of-kin after arrival at hospital.
11
Table 1
Patient characteristics
Number of patients
Age
Cause of cardiac arrest
Initial cardiac rhythm
Collapse to call EMS,#
Call EMS to arrival,#
Arrival EMS to ROSC,#
Total collapse to ROSC,#
ROSC to infusion
commenced,#
Survival (initial rhythm VF)
Survival (initial rhythm not
VF)
22
70 (57, 75)
Presumed cardiac (21)
Overdose of tricyclic antidepressant
(1)
Ventricular fibrillation (14)
Asystole (4)
Pulseless electrical activity (4)
2.0 (1.0, 3.8)
8.0 (6.0, 10.0)
16.0 (7.8, 21.0)
26.0 (20.3, 34.5)
73.0 (50.3, 99.3)
8/14
2/8
Values given as median (interquartile range).
#
Time in minutes.
VF, ventricular fibrillation; ROSC, return of spontaneous circulation; EMS, emergency medical service.
There were no adverse effects of the rapid infusion of
this volume of intravenous crystalloid fluid. In particular, although central venous pressure increased and the
pO2 decreased, no patient developed pulmonary oedema
on either clinical or chest X-ray criteria.
There were 14 patients with an initial rhythm of
ventricular fibrillation of whom eight (57%) were
discharged alive from hospital. Two of eight patients
with an initial cardiac rhythm other than ventricular
fibrillation also survived to hospital discharge. All
deaths occurred subsequent to re-warming in the setting
of severe neurological injury between 18 and 168 h and
these were considered to be unrelated to the initial fluid
therapy.
4. Discussion
3. Results
There were 22 patients enrolled in the study between
March 2000 and May 2002. The demographics of the
patients are shown in Table 1. The mean total collapse
to return of spontaneous circulation time of 27 min
(range 12/48 min) is consistent with our previously
published clinical studies of induced hypothermia [3,4].
The cardiac arrests were witnessed in all 14 patients with
an initial cardiac rhythm of ventricular fibrillation and
four of the remaining eight patients.
The vital signs and laboratory results before and after
the infusion of cold fluid are shown in Table 2. In
addition to the decrease in core temperature, there were
significant improvements in mean arterial blood pressure, renal function and acid /base measurements.
Recent clinical studies suggest that IH improves
outcome in patients with anoxic brain injury following
resuscitation from out-of-hospital cardiac arrest and is
not associated with adverse side-effects [3 /5]. In a
preliminary study, we used IH in 22 adult patients
with coma following resuscitation from pre-hospital
cardiac arrest [3]. Hypothermia (33 8C) was induced
in the ED using surface cooling with ice packs and
maintained for 12 h in the ICU. Compared with 22
historical controls, outcome was significantly improved
and there were no additional complications.
In a subsequent randomized, controlled trial, we
compared IH in 43 patients with normothermia in 34
patients [4]. Hypothermia was also induced in the ED
using surface cooling with ice packs and maintained for
12 h in the ICU. Outcome at hospital discharge was
12
S. Bernard et al. / Resuscitation 56 (2003) 9 /13
Table 2
Vital signs and laboratory investigations immediately pre and post fluid infusion
Temperature, 8C (bladder)
MAP, mmHg
Pulse/min
CVP, mmHg
pH
PO2, mmHg
PCO2, mmHg
Bicarbonate, mmol/l
Sodium, mmol/l
Potassium, mmol/l
Creatinine, mmol/l
Hematocrit, %
Pre fluid
Median (IQR)
Post fluid
Median (IQR)
Difference
(95% CI)
P value
35.5 (35.1, 35.9)
83 (74, 100)
86 (66, 106)
7 (5, 10)
7.28 (7.18, 7.34)
386 (217, 454)
39 (33, 42)
18 (16, 21)
137 (136, 141)
4.0 (3.6, 4.3)
130 (116, 150)
0.38 (0.36, 0.43)
33.8 (33.4, 34.4)
103 (82, 113)
80.5 (67, 93)
12 (8, 15)
7.30 (7.25, 7.40)
187 (89, 391)
37 (32, 41)
21 (16, 22)
138 (137, 141)
4.0 (3.3, 4.2)
105 (88, 125)
0.38 (0.33, 0.41)
1.6 (2.0, 1.1)
10 (2, 14)
5 (15, 4)
4 (1.0, 10)
0.04 (0.01, 0.10)
79 (257, 34)
3 (8, 0)
1.0 (0, 3)
0 (2, 1.0)
0.1 (0.4, 0.3)
20 (36, 13)
0.01 (0.02, 0.01)
B 0.001
0.012
0.091
0.050
0.014
0.025
0.049
0.009
0.586
0.986
0.002
0.134
Median difference, confidence intervals calculated using the binomial exact method.
IQR, interquartile range; CI, confidence intervals.
significantly improved, with 21/43 (49%) of the hypothermia patients discharged to home or rehabilitation
compared with 9/34 (26%) of the normothermic patients. After correction for baseline differences, the odds
ratio for improved outcome using hypothermia was 5.25
(95% confidence intervals 1.47 /18.76). Surface cooling
using ice-packs in both studies was associated with a
rate of core temperature decrease of 0.9 8C/h.
In a multi-center European study, 273 patients who
were resuscitated from out-of-hospital cardiac arrest
were randomized to hypothermia (32 /34 8C for 24 h)
using surface cooling with a cold air blanket [5]. The
outcome at six months after hospital discharge in the IH
group was significantly improved, with 75/136 (55%) of
the hypothermia patients having a favorable neurological outcome compared with 54/137 (39%) of the
normothermic patients. However, surface cooling using
a cold air blanket was associated with a temperature
decrease of only 0.3 8C/h. Other studies of surface
cooling in surgical patients [9,10] have confirmed that
surface cooling is a relatively slow technique to decrease
core temperature.
Since there is evidence in animal studies of significantly reduced anoxic neurological injury if hypothermia is induced immediately after cardiac arrest [6,7], the
development of techniques for the rapid induction of
hypothermia may further improve neurological outcome
after resuscitation from cardiac arrest. One alternative
to surface cooling is the use of a large volume of ice-cold
intravenous crystalloid fluid. This has been studied in
elective surgical patients [11] and healthy volunteers
[12,13]. In a study of elective surgical patients, Baumgardner et al., administered small volume (5 ml/kg) of
5% cold (1 /4 8C) albumin solution intravenously [11].
Core temperature decreased by 0.6 8C (9/0.1 8C)
following rapid (/100 ml/min) infusion, but this
decrease was less (0.4 8C) following slow intravenous
infusion. The effect of large volume, ice-cold fluid
intravenous infusion for the induction of moderate
hypothermia has also been studied in anaesthetized
volunteers by Rajek et al. who infused 40 ml/kg 0.9%
saline solution over 30 min in nine subjects [12]. Using
4 8C fluid, the mean decrease in core temperature was
2.5 8C (9/0.4), which was 0.4 8C more than expected if
the fluid was distributed evenly. In a similar study,
Frank et al. examined age related differences in core
cooling using large volume (40 ml/kg) cold intravenous
fluid in eight young (18 /23 years) and eight older
volunteers (55 /71 years) [13]. The older subjects had a
greater decrease in core temperature at the end of the
infusion (35.0 8C compared with 35.9 8C), possibly
because of decreased thresholds for vasoconstriction,
heat production and catecholamine release.
However, the results of the above studies undertaken
in elective surgical patients or healthy volunteers may
not be applicable to patients who have been resuscitated
from prolonged cardiac arrest with possible severe
myocardial dysfunction. The infusion of a large volume
of intravenous fluid in such patients would be expected
to cause pulmonary oedema, however, this did not occur
in any patient in this study.
Our preliminary report suggests that mild hypothermia may be rapidly and safely induced using 30 ml/kg of
ice-cold fluid in patients who have been resuscitated
from out-of-hospital cardiac arrest. The decrease in core
temperature of 1.6 8C is likely to provide significant
cerebral protection if administered shortly after resuscitation from cardiac arrest [3,4]. In addition, the increase
in mean arterial blood pressure might also be beneficial
in patients with anoxic encephalopathy [14]. The significant decrease in systemic oxygen pressure is not
clinically important, since this decrease would lead to a
minimal change in oxygen content of arterial blood. The
small patient numbers in this preliminary report pre-
S. Bernard et al. / Resuscitation 56 (2003) 9 /13
clude an assessment of the effect of this therapy on
outcome, however the finding that 8/14 patients (57%)
with an initial rhythm of ventricular fibrillation were
discharged home from hospital is encouraging.
This study has a number of limitations. There was no
control group to compare changes in core temperature,
blood pressure, renal function and acid /base if largevolume, ice-cold fluid was not given. However, in
previous studies [3,4], we had not observed spontaneous
decreases in temperature without active cooling efforts.
Whilst improvements in blood pressure, renal function
and acid /base may occur with recovery of the circulation and oxygenation, we have not previously noted
such rapid changes occurring during the time of this
study (mean 73 min after return of the circulation).
The small sample size of this study precludes any
assessment of this technique on outcome. Nevertheless,
we consider the results sufficiently encouraging and
propose that further studies be undertaken in the ED
and out-of-hospital setting. For the latter, paramedics
could administer large volume, ice-cold fluid immediately after resuscitation of patients from cardiac arrest
and, if this is shown to be feasible and safe, further
studies comparing this approach with surface cooling in
the ED could be undertaken.
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