Cardiovascular Research 2001 51(3):529-541; doi:10.1016/S0008-6363(01)00262-0
© 2001 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Employing vasopressin during cardiopulmonary resuscitation and vasodilatory shock as a lifesaving vasopressor
Volker Wenzel* and
Karl H. Lindner
Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University, Anichstrasse 35, 6020 Innsbruck, Austria
* Corresponding author. Tel.: +43-512-504-2400; fax: +43-512-504-5744 volker.wenzel{at}uibk.ac.at
Received 8 November 2000; accepted 29 January 2001
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Abstract
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Epinephrine during cardiopulmonary resuscitation (CPR) is being
discussed controversially due to its β-receptor mediated
adverse effects such as increased myocardial oxygen consumption,
ventricular arrhythmias, ventilation-perfusion defect, postresuscitation
myocardial dysfunction, ventricular arrhythmias and cardiac
failure. In the CPR laboratory simulating adult pigs with ventricular
fibrillation or postcountershock pulseless electrical activity,
vasopressin improved vital organ blood flow, cerebral oxygen
delivery, resuscitability, and neurological recovery better
than did epinephrine. In paediatric preparations with asphyxia,
epinephrine was superior to vasopressin, whereas in both paediatric
pigs with ventricular fibrillation, and adult porcine models
with asphyxia, combinations of vasopressin and epinephrine proved
to be highly effective. This may suggest that a different efficiency
of vasopressors in paediatric vs. adult preparations; and different
effects of dysrhythmic vs. asphyxial cardiac arrest on vasopressor
efficiency may be of significant importance. Whether these theories
can be extrapolated to humans is unknown at this point in time.
In patients with out-of-hospital ventricular fibrillation, a
larger proportion of patients treated with vasopressin survived
24 h compared with patients treated with epinephrine; during
in-hospital CPR, comparable short-term survival was found in
groups treated with either vasopressin or epinephrine. Currently,
a large trial of out-of-hospital cardiac arrest patients being
treated with vasopressin vs. epinephrine is ongoing in Germany,
Austria and Switzerland. The new CPR guidelines of both the
American Heart Association, and European Resuscitation Council
recommend 40 U vasopressin intravenously, and 1 mg epinephrine
intravenously as equally effective for the treatment of adult
patients in ventricular fibrillation; however, no recommendation
for vasopressin was made to date for adult patients with asystole
and pulseless electrical activity, and paediatrics due to lack
of clinical data. When adrenergic vasopressors were unable to
maintain arterial blood pressure in patients with vasodilatory
shock, continuous infusions of vasopressin (
0.04 to
0.1 U/min)
stabilised cardiocirculatory parameters, and even ensured weaning
from catecholamines.
KEYWORDS Adrenergic (ant)agonists; Defibrillation
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1 Epinephrine's 100 year history for CPR turns out to be controversial
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Morbidity and mortality after successful resuscitation from
cardiac arrest largely depends on recovery of neurologic function
[1]. Accordingly, efficiency of an intervention during cardiopulmonary
resuscitation (CPR) has to be judged with regard to its effects
on neurologic outcome
[2]. The American Heart Association
[3] and the European Resuscitation Council
[4] have acknowledged
a lack of clinical evidence to recommend epinephrine during
CPR in previously published guidelines; however, no change was
made in the 1992 and 1998 recommendations due to a lack of proven
alternative drugs or interventions.
Laboratory studies employing epinephrine during CPR showed increased β-receptor-mediated myocardial oxygen consumption [5], ventricular arrhythmias [6], a ventilation-perfusion defect [7] that was possibly caused by attenuated hypoxic pulmonary vasoconstriction [8], postresuscitation myocardial dysfunction, ventricular arrhythmias, and cardiac failure [9]. Another explanation for the adverse effects of epinephrine during CPR is a significant reduction of the myocardial action potentials; it was shown that epinephrine increased the probability that re-entry action potentials hit excitable tissue, which may provoke or even stabilise ventricular fibrillation [10].
In one clinical study from Australia, epinephrine did not result in better short-term survival or hospital discharge rate compared with saline placebo [11]. Further, high-dose epinephrine did not improve hospital discharge rates in several large multicenter clinical trials [12–17]. In a study in the Vienna General Hospital [18], patients with an unfavourable vs. favourable cerebral performance category received a cumulative dose of 4 vs. 1 mg epinephrine during CPR; this finding persisted after stratification by duration of resuscitation. Accordingly, it is disappointing that a drug such as epinephrine, which is being used for resuscitation for more than 100 years [19,20], has controversial safety and efficacy. Given these potential adverse epinephrine-mediated effects, an American researcher asked in an editorial [21] "have we ridden the adrenergic horse as far as it will take us?"
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2 Vasopressin, an endogenous stress hormone
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Vasopressin, a hormone that is called an antidiuretic hormone
as well, has a long evolutionary history. With the emergence
of life on land, vasopressin became the mediator of a remarkable
regulatory system for the conservation of water. Natural vasopressin
forms are nonapeptides with two cysteine residues forming a
bridge between positions one and six. The integrity of this
disulfide bond is essential for its biological activity, and
amino acid substitutions dictate physiologic actions such as
alterations of antidiuretic, or vasopressor function. Interestingly,
vasopressor effects were observed as early as 1895; vasopressin
acts directly via V
1-receptors on contractile elements —
an effect that cannot be reversed by adrenergic blockade or
denervation
[22] (
Table 1). Primary indication of vasopressin
and its analogues so far is management of hypothalamic diabetes
insipidus, and treating bleeding esophageal varices in some
cases.
A number of fundamental endocrine responses of the human body
to cardiac arrest and CPR have been investigated in the past
10 years
[23–25]. Circulating endogenous vasopressin concentrations
were high in patients undergoing CPR, and levels in successfully
resuscitated patients have been shown to be significantly higher
than in patients who died (
Table 2)
[26]. This may indicate
that the human body discharges vasopressin as an adjunct vasopressor
to epinephrine in life-threatening situations such as cardiac
arrest in order to preserve homeostasis. In a clinical study
of 60 out-of-hospital cardiac arrest patients, parallel increases
in plasma vasopressin and endothelin during CPR were found only
in surviving patients. Both before and after epinephrine administration,
plasma epinephrine and norepinephrine concentrations were significantly
higher in patients who died when compared with surviving cardiac
arrest victims
[27]. Thus, plasma concentrations of vasopressin
may have a more important effect on CPR outcome than previously
thought; and prompted several investigations to assess its role
for possible CPR management in order to improve CPR management.
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3 Vasopressin during CPR in laboratory models: assessment of individual organ function
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During ventricular fibrillation, a dose–response investigation
of three vasopressin dosages (0.2, 0.4, 0.8 U/kg) compared with
the maximum effective dose of 200 µg/kg epinephrine showed
that 0.8 U/kg vasopressin was the most effective drug in regards
of increasing vital organ blood flow
[28] (
Fig. 1). Also, vasopressin
significantly improved cerebral oxygen delivery, and ventricular
fibrillation mean frequency during CPR when compared with a
maximum dose of epinephrine
[29] (
Figs. 2–4
). Furthermore,
effects of vasopressin on vital organ blood flow lasted longer
after vasopressin than after epinephrine (
4 vs.
1.5 min); significantly
more vasopressin animals could be resuscitated; and vasopressin
did not result in bradycardia after return of spontaneous circulation
(
Fig. 5)
[30]. Interestingly, the combination of vasopressin
and epinephrine vs. vasopressin only resulted in comparable
left ventricular myocardial blood flow, but in significantly
decreased cerebral perfusion
[31]. The binding of both vasopressin
and epinephrine to its receptors causes characteristic changes
such as intracellular concentration of phosphatidylinositol
and calcium
[32,33]. In fact, a rodent study evaluating administration
of vasopressin, norepinephrine, and a combination of vasopressin
and norepinephrine showed that V
1- and
-adrenergic receptors
saturated the same intracellular transduction pathway
[34].
Although speculative, this mechanism may have hampered nitric
oxide release in the cerebral vasculature induced by vasopressin,
and therefore, suppressed cerebral perfusion in our animals
receiving a combination of vasopressin and epinephrine. These
results are striking, since epinephrine selectively spares the
cerebral circulation from vasoconstriction when administered
during CPR alone.
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Fig. 1 Systemic vascular resistance during closed-chest cardiopulmonary resuscitation (CPR) in pigs before, 90 s after, and 5 min after administration of 200 µg/kg epinephrine, 0.2 U/kg vasopressin (low dose), 0.4 U/kg vasopressin (medium dose), and 0.8 U/kg vasopressin (high dose), and in the 1-h postresuscitation phase. Each bar represents the mean±S.E.M. of seven observations. **, P<0.01, ***, P<0.001 between epinephrine and 0.8 U/kg vasopressin groups. VF, ventricular fibrillation; Defib, defibrillation; and ROSC, restoration of spontaneous circulation. Note that 0.8 U/kg vasopressin increases systemic vascular resistance during CPR fundamentally to levels of 10 000 dyness–1cm–5, which shifts blood flow from muscle, skin and gut towards the heart and brain. Reprinted with permission from Lindner et al., Circulation 1995;91:215–221. Copyright 1995 American Heart Association.
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Fig. 3 Cerebral oxygen delivery and consumption indices, and oxygen extraction ratio during cardiopulmonary resuscitation before, and 90 s and 5 min after intravenous administration of 200 µg/kg epinephrine (maximum effective dosage in pigs;  ) and 0.4 U/kg vasopressin (medium dosage in pigs;  ). Each box plot represents median, 25th and 75th percentiles, and minimum and maximum values. *, P<0.05 vs. epinephrine;  , P<0.01 vs. epinephrine;  , P<0.05 vs. before drug administration (DA). Note that the superior cerebral blood flow with vasopressin lead to a greater cerebral oxygen consumption, but this was not the result of an overstimulation of metabolism because cerebral oxygen extraction fell, and oxygen uptake became independent of oxygen delivery. Reprinted with permission from Prengel et al., Stroke 1996;27:1241–1248. Copyright 1996 American Heart Association.
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Fig. 4 Power spectrum and 10 s ECG ventricular fibrillation pattern of a laboratory pig during basic life support CPR (before vasopressin), and during advanced cardiac life support CPR 90 s after vasopressin. Note that vasopressin induces an increase of ventricular fibrillation mean frequency, which is validated by the rightward shift of the power spectrum (a, c); and increase in ECG amplitude (b, d). Reprinted with permission from Achleitner et al., Anesth Analg 2000;90:1067–1075. Copyright International Anesthesia Research Foundation 2000.
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Fig. 5 Porcine laboratory model of prolonged cardiac arrest of 15 min with postcountershock pulseless electrical activity. Left ventricular myocardial, and total cerebral blood flow before, 90 s, and 5 min after vasopressin () or epinephrine () administration during CPR. Each box plot represents median, 25th and 75th percentiles, and minimum and maximum values of eight measurements in both groups; *, P<0.05 vs. vasopressin. Note that vasopressin during CPR may increase myocardial blood flow to 60% of prearrest values (normal left ventricular myocardial blood flow in pigs, 200 ml/min/100 g), but brain perfusion even to 150% of prearrest values (normal brain blood flow in pigs, 50 ml/min/100 g). Reprinted with permission from Wenzel et al., Crit Care Med 1999;27:486–492. Copyright Lippincott Williams & Wilkins 1999.
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Administration of endobronchial drugs during CPR may be a simple
and rapid alternative, when intubation is performed before intravenous
cannulation
[35], when the time interval for intravenous access
is prolonged, or when attempts for intravenous access are simply
unsuccessful, such as in young children with poor peripheral
perfusion. A laboratory model showed that the same dose of intravenous
and endobronchial vasopressin resulted into the same coronary
perfusion pressure four min after drug administration
[36] (
Fig. 6).
In contrast, the equipotent endobronchial epinephrine dose is
approximately ten times higher than the intravenous epinephrine
dose during CPR
[37]. This investigation showed that endobronchial
vasopressin is absorbed during CPR, increased coronary perfusion
pressure significantly within a very short period, and increased
the chance of successful resuscitation
[39]. However, endobronchial
drug administration may be less appropriate in children, who
suffer cardiac arrest due to respiratory disorders. For example,
in children suffering cardiac arrest mostly due to severe pneumonia,
endobronchial drug delivery is not likely to result in adequate
drug absorption, and therefore, may be rather ineffective. In
such cases, the endobronchial drug delivery route may render
drug absorption erratic due to pulmonary oedema and capillary
leak, and therefore, may further compromise oxygenation and
ventilation in children
[38]. Additionally, hypovolemia can
be rapidly corrected with fluids via an intraosseous catheter,
but not via the endobronchial route. Accordingly, the intraosseous
route has been recommended for paediatric emergency situations,
and is widely taught both in the Americas and internationally
by the Paediatric Advanced Life Support and Advanced Trauma
Life Support courses
[39]. In a porcine investigation, intraosseous
vs. intravenous vasopressin resulted in comparable vasopressin
plasma levels, hemodynamic variables, coronary perfusion pressure,
and return of spontaneous circulation rates
[40] (
Fig. 7). Therefore,
intraosseous vasopressin may be a valuable alternative for vasopressor
administration during CPR, when intravenous access is delayed,
or not available. Accordingly, our laboratory studies indicate
that the same vasopressin dosage may be administered intravenously,
endobronchially, and intraosseously; rendering usage of this
vasopressor during CPR simple, rapid and inexpensive.
Both the American Heart Association and European Resuscitation
Council continue to recommend repeated administration of epinephrine
during advanced cardiac life support
[56,57], although it is
not proven whether repeated epinephrine given during CPR may
be effective, or if this strategy may even result in inadvertent
catecholamine toxicity. After repeated dosages of vasopressin
vs. epinephrine were administered, coronary perfusion pressure
increased only after the first of three epinephrine injection,
but increased after each of three vasopressin injections; accordingly,
all vasopressin animals survived; whereas all pigs resuscitated
with epinephrine died
[41]. Long-term survival after cardiac
arrest may be determined by the ability to ensure adequate organ
perfusion during CPR, and in the postresuscitation phase. In
the early postresuscitation phase, vasopressin administration
resulted in higher arterial blood pressure, but a lower cardiac
index; a reversible depressant effect on myocardial function
of the vasopressin pigs was observed when compared with epinephrine.
However, overall cardiovascular function was not irreversibly
or critically impaired after the administration of vasopressin
[42]. Renal and splanchnic perfusion may be critically impaired
during
[43,44] and after
[45] successful resuscitation from
cardiac arrest. For example, 30 min after return of spontaneous
circulation, renal and adrenal blood flow were significantly
lower in the vasopressin pigs as compared with the epinephrine
group; pancreatic, intestinal, and hepatic blood flow were not
significantly different in animals after receiving epinephrine
or vasopressin
[46]. It is unknown whether the vasopressin-mediated
pronounced blood shift during CPR from the muscle, skin and
gut towards the myocardium and brain might be deleterious for
splanchnic organs, and whether this may contribute to multiorgan
failure after return of spontaneous circulation. Furthermore,
it is unknown whether a high bolus of vasopressin administered
during CPR may result in oliguria or anuria due to its antidiuretic
effects in the postresuscitation phase. In a porcine CPR investigation,
vasopressin impaired cephalic mesenteric blood flow during CPR
and in the early postresuscitation phase, but did not result
in an anti diuretic response. Neither renal blood flow, nor
renal function was influenced by vasopressin or epinephrine
in this investigation
[47]. Continuous infusion of low-dose
dopamine mediated a significant increase in superior mesenteric
blood flow after successful CPR with vasopressin by selective
vasodilatation of intestinal vessels. Accordingly, administering
dopamine may improve gut perfusion, and therefore, may improve
gut function in the postresuscitation period
[48].
In laboratory investigations of short and prolonged cardiac arrest, vasopressin resulted in significantly higher vital organ blood flow and cerebral oxygen delivery than did epinephrine [28–31]. This implies that vasopressin dilated cerebral arterioles and subsequently, resulted in superior brain perfusion throughout the neuroaxis. In the vasopressin animals, the superior cerebral blood flow lead to a greater cerebral oxygen consumption, but was not the result of an overstimulation of metabolism because cerebral oxygen extraction fell, and oxygen uptake became independent of oxygen delivery [29]. The question arises, if increased cerebral blood flow during CPR with vasopressin is beneficial in regards of neurological recovery, or detrimental due to fatal complications such as cerebral oedema after return of spontaneous circulation. Although a Glasgow-Coma Score rating was performed after successful CPR with vasopressin vs. epinephrine in preliminary clinical studies, the results could unfortunately not be attributed to a single CPR-intervention due to many confounding variables. In a porcine model simulating prolonged (22 min) of advanced cardiac life support, all vasopressin animals had return of spontaneous circulation, whereas all pigs in the epinephrine and saline placebo group died. After 24 h of return of spontaneous circulation, the only neurologic deficit of all vasopressin pigs was an unsteady gait, which disappeared within another 3 days [49]. This observation confirms that in order to achieve full recovery after cardiac arrest, both excellent management of basic and advanced cardiac life support, and careful optimisation of organ function in the postresuscitation phase are of fundamental importance. (Fig. 8) [50] Since neurodiagnostic tests such as evoked potentials, electroencephalogram, or positron emission tomography may not be able to accurately detect pathology [51], we employed cerebral magnetic resonance imaging after successful CPR. Since imaging was performed 4 days after the experiment to ensure that cerebral ischemic regions due to extracellular edema would be fully developed, the absence of cerebral cortical and subcortical edema, intraparenchymal haemorrhage, ischemic brain lesions, or cerebral infarction confirmed by T2-weighted magnetic resonance imaging indicates that the vasopressin pigs fully recovered from cardiac arrest in regards of both anatomical and physiological terms. Thus, laboratory evidence suggests that vasopressin given during CPR may be a superior drug when compared with epinephrine in order to ensure both return of spontaneous circulation and neurological outcome.
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Fig. 8 Effects of vasopressin, epinephrine, and saline placebo on diastolic aortic pressure during prolonged advanced cardiac life support CPR. Repeated doses of vasopressin ( ), but not epinephrine () or saline placebo ( ), maintained mean±S.E.M. aortic diastolic arterial blood pressure above a threshold of about 30 to 40 mmHg (horizontal dashed lines) that renders successful defibrillation likely. DA 1 indicates drug administration of 0.4 U/kg vasopressin vs. 45 µg/kg epinephrine vs. saline placebo; DA 2, drug administration of 0.4 U/kg vasopressin vs. 45 µg/kg epinephrine vs. saline placebo; DA 3, drug administration of 0.8 U/kg vasopressin vs. 200 µg/kg epinephrine vs. saline placebo; *, P<0.05 vs. epinephrine and saline placebo, respectively;  , P<0.05 vs. saline placebo; ACLS, advanced cardiac life support; BLS, basic life support; VF, ventricular fibrillation; time is given in min (') and seconds (''). Note that only the first of three epinephrine injections, but three of three vasopressin injections maintained coronary perfusion pressure at a level that ensured return of spontaneous circulation: Six of six vasopressin pigs survived with full neurological recovery, whereas both six of six epinephrine- and five of five saline placebo pigs died. Reprinted with permission from Wenzel et al., J Am Coll Cardiol 2000;35:527–533. Copyright American College of Cardiology 2000.
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4 Clinical experience with vasopressin during cardiac arrest
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In patients with refractory cardiac arrest, intravenous vasopressin
induced an increase in arterial blood pressure, and in some
cases, return of spontaneous circulation, where standard therapy
with chest compressions, ventilation, defibrillation, and epinephrine
had failed
[52]. In a small (
n=40) prospective, randomised investigation
of patients with out-of-hospital ventricular fibrillation, a
significantly larger proportion of patients treated with vasopressin
were successfully resuscitated and survived 24 h compared with
patients treated with epinephrine
[53]. This was not designed
as a mortality study, but even with such small numbers, there
was a non-significant trend towards an improvement in hospital
discharge rate (
P=0.16). In a large (
n=200) in-hospital CPR
trial from Ottawa, Canada, comparable short-term survival was
found in both groups treated with either vasopressin or epinephrine,
indicating that these drugs may be equipotent when response
times of rescuers are short
[54]. In another clinical evaluation
in Detroit, Michigan, four of ten patients responded to vasopressin
administration after approximately 40 min of unsuccessful advanced
cardiac life support, and had a mean increase in coronary perfusion
pressure of 28 mmHg
[55]. This is surprising, since an arterial
blood pressure increase with any drug after such a long period
of non-effective CPR management would be normally not expected.
In this study, vasopressin caused an increase in coronary perfusion
pressure, and a decrease of epinephrine plasma levels, which
is similar to an animal study with increased vital organ blood
flow, but decreased catecholamine plasma levels after vasopressin
[56]. Although speculative, it is possible that baroreceptors
in the arterial vasculature registered increased organ perfusion
after vasopressin, and subsequently down-regulated catecholamine
secretion — whether this may decrease epinephrine tachyphylaxis
and therefore, improve subsequent catecholamine effects, remains
under investigation.
The authors of the present article are currently co-ordinating a multicenter clinical study to determine the effects of 40 U vasopressin IV vs. 1 mg epinephrine IV given up to two times in out-of-hospital cardiac arrest patients with ventricular fibrillation, asystole, and pulseless electrical activity (Fig. 9). This clinical trial is conducted under the aegis of the European Resuscitation Council, and has randomised per March, 2001 a total of 770 patients in 42 EMS systems (37 ground, and 5 rotor-winged EMS programs) in Germany, Switzerland, and Austria. A preliminary analysis has revealed that the study is safe, randomisation is working properly, no adverse results were reported, and that there is a good chance to find significant results after randomising 1500 patients as planned. The new international CPR guidelines of both the American Heart Association [57] and European Resuscitation Council [58] recommend 40 U vasopressin IV and 1 mg epinephrine IV as equally effective for the treatment of patients in ventricular fibrillation; however, no recommendation was made to date for patients with asystole and pulseless electrical activity, and paediatrics due to lack of clinical data. When the aforementioned large clinical study may be concluded in Autumn 2001, we may be able to better determine the role of vasopressin vs. epinephrine for management of cardiac arrest patients presenting with ventricular fibrillation, asystole, or pulseless electrical activity [59].
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Fig. 9 Study algorithm of a multicenter, blockrandomized, doubleblind, randomized controlled trial in Europe: comparison of vasopressin vs. epinephrine during cardiac arrest. A study conducted under the aegis of the European Resuscitation Council. Reprinted with permission from Krismer et al. (article in German) Notfall Rettungsmed 1999;2:478–485. Copyright Springer Verlag, Berlin, Heidelberg, New York, 1999.
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Efficiency of a CPR intervention is judged with regards to its
effects on hospital discharge rate, long-term survival, and
especially, neurologic outcome. However, in order to determine
effects of a drug given during CPR on neurological recovery
is extremely difficult due to confounding variables. For example,
a given patient population differs significantly due to past
medical history, standard of life, age, race, cardiac rhythm
at collapse, and location of cardiac arrest
[60,61]. Second,
the healthcare system itself may affect CPR outcome fundamentally
due to differences in emergency medical services, response times,
intensive care unit management, and access to diagnostic technology
[62]. In order to detect a significant increase in hospital
discharge rates and/or neurological recovery employing a new
pharmacological CPR intervention,
20 000 patients, several years,
and millions of US Dollars or Euros would be necessary —
a trial that would be significantly bigger than large Framingham
Heart studies with typically
3000
[63] to
5000 patients
[64].
Thus, initiating such as study seems to be almost next-to-impossible,
since healthcare and research funding is decreasing throughout
the world; further, commercial manufacturers of vasopressin
have not much interest in this drug since the patent of vasopressin
has expired
50 years ago. As such, the primary endpoint of the
European vasopressor study (anticipated number of patients,
1500) are effects of vasopressin vs. epinephrine on hospital
admission — not the optimum, but a realistic solution.
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5 Where is the future of CPR management?
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We have shown beneficial effects of vasopressin vs. epinephrine
in special CPR situations such as epidural anaesthesia
[65],
hypothermia
[66], and hypovolemic shock
[67] in the laboratory.
In the clinical setting, we observed positive effects of vasopressin
infusions in some patients with life-threatening haemorrhagic
shock with collapsing arterial blood pressure, who did not respond
anymore to adrenergic catecholamines. Although these observations
in the laboratory and in individual patients are very promising,
they have to be yet confirmed in prospective, randomised clinical
trials; however, due to the relatively rare occurrence of these
special CPR situations, it is unlikely that vasopressin can
be studied systematically under these circumstances.
Another area that is extremely complicated to investigate, but definitely needs to be addressed, is the paediatric cardiac arrest population. Due to the lack of randomised clinical trials in paediatric emergency cardiac care, some CPR recommendations have been extrapolated from adult or laboratory studies. In a porcine preparation, epinephrine was superior to vasopressin in a paediatric CPR model of asphyxia cardiac arrest [68]. We have shown in this paediatric model that a combination of vasopressin and epinephrine was superior to either vasopressin or epinephrine alone; however, this may only apply to paediatric but not adult settings, and definitely warrants especially clinical investigations. Upon repeating the aforementioned experiment of asphyxia cardiac arrest in adult swine to determine effects of age vs. underlying cause of cardiac arrest, we confirmed that a combination of vasopressin with epinephrine was superior to either vasopressin alone, or epinephrine alone. This observation is entirely new and surprising, and may suggest that the usual approach of pharmacological CPR management to administer identical drugs and dosages for patients presenting with cardiac arrest due to dysrhythmia or asphyxia may have to be reconsidered. In fact, it is possible that when the degree of ischemia is fundamental such as during asphyxia, or advanced cardiac life support is prolonged, a combination of vasopressin with epinephrine could be beneficial. The laboratory experience of this phenomenon may be confirmed by observations from CPR efforts in eight patients who were unsuccessfully resuscitated with epinephrine for 10–20 min, subsequently received 40 U of vasopressin, and subsequently, all patients had return of spontaneous circulation, with three of eight patients being even discharged alive from the hospital [52]. This explanation would be in agreement with a Canadian study [54] indicating comparable outcome with vasopressin vs. epinephrine in in-hospital cardiac arrest, with a short time of ischemia.
Thus, our usual strategy according to the current CPR guidelines of employing vasopressors during CPR may not sufficiently address the cause of cardiac arrest, and degree of ischemia. Accordingly, it is possible that the ideal vasopressor and especially, the ideal dosing regimen for CPR is yet to be discovered, rendering a combination of agents possibly necessary; however, development of a CPR ‘cocktail’ may be extremely difficult due to multiple potential permutations of different drugs and dosages whenever a combination therapy is employed [69]. Laboratory experiments were performed with a combination of vasopressin, epinephrine and nitroglycerine; however, determining optimal dose–response effects is most likely difficult, and clinical experience is pending [70]. Further, vasopressors that improve initial resuscitation may not be the best drugs to improve survival in the post resuscitation phase. The ideal vasopressor for CPR is a drug that significantly increases myocardial and cerebral perfusion during CPR, and yet, if necessary, can be rapidly, but titratibly reversed in the immediate post-resuscitation phase [71]. Although the case of vasopressin looks promising at this point in time, the large clinical study in Europe would have to come out significantly in favour of vasopressin in order to further change international CPR guidelines.
The exciting news about vasopressin studies cannot cover the fact that many issues have not been addressed as of today, at least partially because commercial interest is lacking due to an expired patent from 50 years ago. For example, the only dose–response investigation with vasopressin stems from young healthy pigs; vasopressin experience in humans is solely based on injections of 40 U. Second, preliminary laboratory evidence suggests beneficial effects of a combination of vasopressin with epinephrine in asphyxia cardiac arrest; however, this observation is inconsistent with a report in a postcountershock pulseless electrical activity preparation — further research is necessary which drug plays which role in what situation. Third, vasopressin receptors in pigs (lysine vasopressin) and humans (arginine vasopressin) are different, which may result in a different hemodynamic response to exogenously administered arginine vasopressin. However, the circulatory effects of arginine vasopressin, as administered in all laboratory investigations, may be even greater in humans with arginine vasopressin receptors when compared with pigs with lysine vasopressin receptors. Furthermore, extrapolating experience with vasopressin from the adult to the paediatric setting seems to be difficult, and needs further significant investigation. Also, young healthy pigs that were free of atherosclerotic disease were employed in animal studies; it is therefore difficult to determine whether all laboratory results can be safely extrapolated to humans with sometimes severe underlying cardiovascular pathology upon suffering sudden cardiac arrest. Although preliminary evidence suggests slight coronary vasodilatation after vasopressin administration, this model of extremely low cardiac output such as shock or CPR had the limitation to have a pre- and afterload that may be different from normal cardiocirculatory circumstances due to an open-chest preparation [72]. Lastly, There is no doubt that a CPR attempt employing vasopressin is more expensive than epinephrine (cost of 40 U vasopressin vs. 1 mg epinephrine, 15 vs. 1 US Dollar/Euro); however, this is not as expensive as a day on the intensive care unit on powerful antibiotics. In summary, laboratory studies employing vasopressin administration may have to detect the best time point, dosage, and exact indication for shock states — a lot of time and resource-consuming work is down the road, but as an ‘orphan’ drug, vasopressin has come a long way already.
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6 Vasopressin as a continuous infusion during vasodilatory shock
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The standard treatment of vasodilatory septic shock includes
antibiotics, extracellular volume expansion, vasopressors, and
drugs that increase myocardial contractility. Adrenergic catecholamines
employed in this setting such as norepinephrine often have a
diminished vasopressor action in vasodilatory shock; therefore,
alternatives may be very useful. First reports with vasopressin
in septic shock described a patient who was successfully resuscitated
from cardiac arrest, but subsequently developed bacterial septicaemia,
and needed a continuous infusion of both epinephrine and norepinephrine
to maintain systolic arterial pressure of
90 mmHg (
Fig. 10).
Continuous infusion of vasopressin (0.04 U/min) then easily
improved mean arterial blood pressure, cardiac output remained
stable, and urine output increased from
6 to >50 ml/h. Stepwise
withdrawal of vasopressin subsequently resulted in a decrease
in arterial pressure, which again required norepinephrine to
maintain systolic arterial pressure at 90–100 mmHg; urine
output decreased to 30 ml/h. Six hours later, systolic arterial
pressure was maintained at
105 mmHg on vasopressin alone
[73].
In patients with vasodilatory shock after left ventricular assist
device placement or postbypass vasodilatory shock, vasopressin
(0.1 U/min) increased mean arterial pressure, while norepinephrine
was decreased
[74,75]. In the latter study, inappropriately
low serum vasopressin concentrations were found before vasopressin
administration, indicating endogenous vasopressin deficiency.
Thus, it is possible that endogenous vasopressin stores in these
patients were simply depleted, or not able to meet the demand
to maintain cardiocirculatory homeostasis. Another investigation
studying patients on amiodarone and angiotensin-converting enzyme
inhibitors with refractory vasodilatation after cardiopulmonary
bypass revealed a beneficial potential for continuous vasopressin
infusion
[76]. Similar observations were made in patients with
milrinone-induced hypotension, when 0.03–0.07 U/min vasopressin
caused an increase in systolic artery pressure of from
90 to
130 mmHg
[77].
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|
Fig. 10 Arterial blood pressure, urine output, and vasopressor management of a patient who was successfully resuscitated, but developed septic vasodilatory shock that was refractory to catecholamines. Note that an infusion of vasopressin increased arterial blood pressure, while both epinephrine and norepinephrine could be weaned; when vasopressin was discontinued, epinephrine and norepinephrine were again necessary to maintain arterial blood pressure. Reprinted with permission from Landry et al., Crit Care Med 1997;25:1279–1282. Copyright 1997 Lippincott Williams & Wilkins, Baltimore.
|
|
These observations may be similar to first experiences in cardiac
arrest patients, when high endogenous vasopressin levels correlated
with subsequent survival
[27]. As such, it is likely that vasopressin
in addition to the well established endogenous stress hormone
epinephrine plays an important role in regards of arterial blood
pressure regulation during shock states such as septicaemia,
and CPR. Currently, we do not exactly know whether vasopressin
acts simply as a back-up of the back-up vasopressor epinephrine
during life-threatening shock states, whether vasopressin or
epinephrine alone is better in certain situations, or whether
these two hormones have unique adjunct features that we are
only starting to understand. A better knowledge of these underlying
mechanisms most likely would save many patients; patients who
at this point in time have a relatively small chance of survival.
|
7 Practice points: management of cardiac arrest and vasodilatory shock patients
|
|---|
In adult patients with shock-refractory ventricular fibrillation,
40 U vasopressin, or 1 mg epinephrine should be administered
intravenously; vasopressin is currently a single dosage, epinephrine
can be repeated every 2–5 min. No recommendation for vasopressin
was made to date for adult patients with asystole and pulseless
electrical activity, and paediatrics due to lack of clinical
data. Patients with vasodilatory shock refractory to adrenergic
vasopressors should receive continuous infusions of vasopressin
early (
0.04 to
0.1 U/min) in order to stabilise cardiocirculatory
function.
Time for primary review 21 days.
|
Acknowledgements
|
|---|
Supported, in part, by the Austrian Science Foundation grant
P14169
[GenBank]
-MED, and the Austrian National Bank, both of Vienna,
Austria; a Founder's Grant of the Society of Critical Care Medicine,
Anaheim, California; and the Laerdal Foundation for Acute Medicine,
Stavanger, Norway.
|
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Top
Abstract
1 Epinephrine's 100 year...
); endobronchial vasopressin (
); *, P<0.05 compared with endobronchial saline placebo; 