VASOPRESSIN AND SHOCK
Dr. Paul Forrest
Vasopressin (antidiuretic hormone) is emerging as an important advance in the treatment of a variety of shock states. This has arisen from increased understanding of its importance in the endocrine response to shock. There is current interest in the use of vasopressin in the treatment of shock due to ventricular fibrillation, hypovolaemia, sepsis and cardiopulmonary bypass.
PHYSIOLOGY OF VASOPRESSIN IN SHOCK
Arginine vasopressin is released from the posterior pituitary in response to increased serum osmolality or reduced plasma volume.1,2 Under normal conditions, the major physiological role of vasopressin is the regulation of water balance. It does not appear to play a major role in the vascular regulation of blood pressure and abnormally high endogenous vasopressin levels (syndrome of inappropriate ADH secretion) do not produce hypertension.3
In shock states however, endogenous vasopressin release is an important vasoconstrictor mechanism. In common with other stress hormones such as the catecholamines, hypotension stimulates vasopressin release via activation of aortic and carotid baroreceptors. Patients in cardiac arrest undergoing cardiopulmonary resuscitation (CPR) have very high levels of circulating vasopressin4 (up to 469 pg/ml., normal <5 pg/ml5). Plasma levels of vasopressin increase within a few minutes of circulatory arrest and also rise in response to haemorrhage,6 sepsis 7,8 myocardial infarction,9,10 cardiopulmonary bypass (CPB), 11,12 epidural13 and general anaesthesia,14 surgery 15 and exercise.16 However, prolonged hypovolaemia,17,18 sepsis19 and CPB20,21 may lead to vasopressin levels that are inappropriately low for the given degree of hypotension. This may contribute to the development of pathologic vasodilatation that may occur during advanced shock. The mechanism by which relative vasopressin deficiency occurs is incompletely understood. One explanation is that exhaustion of secretory stores in the neurohypophysis and hypothalamus may occur after prolonged stimulation of vasopressin release. This has been shown to occur in response to other potent stimuli of vasopressin release such as severe hypernatraemia.22,23 Another possibility is that impaired autonomic function may reduce the baroreflex-mediated stimulation of vasopressin release.19,20 Primary autonomic failure has been shown to inhibit the baroflex-mediated secretion of vasopressin24,25 and impaired autonomic function has also been shown to occur in septic shock26 and following CPB.27,28
Cardiovascular actions of exogenous vasopressin
The vascular response to exogenous vasopressin is markedly enhanced by a variety of shock states. For example, doses of vasopressin that have minimal pressor action in normal subjects (~0.02U/min)29,30 may produce marked effects in sepsis31 and haemorrhagic shock.17 The pressor actions of vasopressin in shock results from an overall increase in systemic vascular resistance (SVR), although markedly different responses occur between regional circulations. Blood flow is reduced to skin, skeletal muscle, small bowel and fat and increased to the heart and brain.32-38Blood flow is thereby diverted from non-critical to critical organ beds.
Exogenous vasopressin produces complex cardiac effects that are a mixture of direct and reflex actions.39In the isolated heart, low Šdose vasopressin is a positive inotrope.40 However in vivo, vasopressin decreases cardiac output in patients with normal hearts or mild heart failure, presumably as a reflex response to an increase in SVR.41,42 High dose vasopressin decreases cardiac output by producing coronary vasoconstriction.43In an animal model of chronic heart failure, the vascular response to exogenous vasopressin was increased compared to controls despite the occurrence of normal endogenous levels.38 This suggests that increased vascular responsiveness to endogenous vasopressin may contribute to the increase in SVR produced by heart failure.
Unlike adrenaline, vasopressin administration does not adversely affect renal blood flow during animal models of shock . Renal blood flow was increased in response to vasopressin infusion during haemorrhage44 and severe heart failure,39 and was unaffected by low and high-dose bolus administration during CPR.32
The actions of vasopressin on the splanchnic circulation may be affected by haemorrhage. Normally, portal venous pressures fall in response to reduced splanchnic blood flow. This is the mechanism by which vasopressin reduces variceal bleeding.45-7 The magnitude of this response is reduced by haemorrhage.48
The pressor actions of vasopressin are complex and incompletely understood. Vasopressin acts via specific renal (V-2) and vascular (V-1) receptors although vascular vasopressin receptors are not as well characterised as are adrenergic receptors.
Vasopressin produces vasoconstriction in non-vital circulations by activation of V-1 receptors. In common with the a- adrenergic agonists, V-1 activation leads to increased levels of the second Šmessengers inositol phosphate and diacylglycerol, which in turn activate voltage-gated calcium channels. This results in increased intracellular calcium levels, causing vasoconstriction.49
How vasopressin produces vasoconstriction in some vascular beds and vasodilation at others is unclear, but the mechanism is related to endothelial nitric oxide (NO). Vasopressin has been shown to produce vasodilation in the renal,50pulmonary,37mesenteric51,52 and especially in the cerebral vascular beds33-35 by stimulating endothelial NO release.
Although vasopressin has similar pressor actions to the catecholamines, it also has unique actions in reversing some of the pathologic vasodilatory processes that occur in advanced shock (which may be refractory to catecholamine vasopressors). There are two mechanisms by which this has been shown to occur. Firstly, vasopressin inhibits ATP Šsensitive potassium channels (KATP) in vascular smooth muscle.53Tissue hypoxia or hypoperfusion due to hypovolaemia and septic shock has been shown to activate KATP channels.54,55Activation of KATP channels produces cellular hyperpolarisation which in turn inhibits voltageŠgated calcium channels. Intracellular calcium levels fall, resulting in vasodilation.53 Secondly, vasopressin inhibits the inflammatory cytokine interleukin 1-§.56 Interleukin 1-§ is released in response to trauma or infection57,58and produces vasodilation by stimulating vascular endothelial NO production.56The mechanism by which vasopressin inhibits interleukin-1-§ is unknown but it has been shown to be mediated by V-1 receptor activation.
In summary, the pressor actions of exogenously administered vasopressin in shock result not only from the restoration of impaired vasoconstrictor mechanisms (due to correction of relative vasopressin deficiency) but also from the inhibition of pathological vasodilator responses.
Recent studies questioning the value of adrenaline during CPR have lead to the search for alternative pressor agents. Standard and high dose adrenaline did not lead to better short-term survival than placebo in one study67 and high dose adrenaline has not been to shown to improve survival over standard dose.68-70In addition, the §-adrenergic properties of adrenaline may increase myocardial injury after successful resuscitation by worsening the imbalance between myocardial oxygen supply and demand.71Interest in the use of vasopressin as a therapy for ventricular fibrillation was triggered by the observation that vasopressin levels were significantly higher in resuscitated than in nonresuscitated patients undergoing CPR for out- of -hospital cardiac arrest.4
During ventricular fibrillation and closed-chest CPR, vasopressin 0.8U/kg produced significantly higher coronary perfusion pressure, myocardial and cerebral blood flow than did adrenaline 200µg/kg.32In addition, vasopressin was longer acting than adrenaline: 5 minutes after adrenaline administration left ventricular and cerebral blood flow remained elevated only 29% and 22% above baseline (respectively), for vasopressin the respective increases were 217% and 111%. Renal blood flow did not significantly differ between the groups, however vasopressin 0.8U/kg lead to a greater reduction in nonvital organ flow (skeletal muscle, small intestine and fat) than did adrenaline 200µg/kg.
The same research group demonstrated in two further studies that during prolonged cardiac arrest, vasopressin produced significantly better cardiovascular and neurological recovery than did adrenaline. In the first, 18 pigs were subjected to 15 minutes of cardiac arrest followed by 3 minutes of CPR. Either vasopressin 0.8U/kg or adrenaline 200µg/kg was then administered before defibrillation was attempted. Vasopressin produced greater increases in myocardial and cerebral blood flow than did adrenaline and return to spontaneous circulation was achieved in 8/9 vasopressin treated pigs but in only 1/9 of the adrenaline group (p<0.05).72In the second study, ventricular fibrillation was induced in 17 pigs. After 4 minutes of cardiac arrest, basic CPR was performed for 3 minutes followed by a further 15 minutes of CPR- during which time the pigs received every 5 minutes either vasopressin (0.4, 0.4,0.8U/kg), adrenaline (45, 45, 200µg/kg) or placebo. Defibrillation was then attempted after 22 minutes in cardiac arrest. All of the 6 adrenaline and 5 placebo treated pigs died, whereas all 6 vasopressin pigs survived (p<0.05). Most impressively, these surviving pigs were essentiallly neurologically intact at 24 hours. They had only an unsteady gait, while MRI examination revealed no cerebral pathology.73
Is there a potential synergistic action between vasopressin and adrenaline during CPR? In pigs undergoing CPR, a combination of vasopressin 0.3U/ kg and adrenaline 40ug/kg resulted in a more rapid rise in coronary perfusion pressure than did either agent given alone.74However, two minutes after drug administration, coronary blood flow did not differ significantly between groups, while the cerebral blood flow in the vasopressin-alone group was more than twice that of both the adrenaline Šalone group (0.76 vs.0.3ml/min/g, p<0.01) and of the vasopressin+adrenaline group (0.76 vs. 0.23ml/min/g, p<0.01). The haemodynamic effects of vasopressin alone or in combination with adrenaline outlasted those of adrenaline alone, although the duration of action did not differ between the vasopressin-alone and vasopressin+adrenaline group. These results indicate that the addition of adrenaline to vasopressin did not confer any significant clinical benefit.
Vasopressin was also shown to be effective during hypothermic cardiac arrest.75Resuscitation of 15 pigs who had undergone 30 minutes of untreated cardiac arrest at 26C was attempted after vasopressin, adrenaline or placebo administration. Vasopressin 0.4U/kg produced higher coronary perfusion than adrenaline 45µg/kg and comparable pressures to high dose adrenaline (200ug/kg). Spontaneous circulation could be restored in 3/5 adrenaline and 3/5 vasopressin Štreated pigs, but in none of the placebo group.
Intraosseous 76 and endobronchial77 administration of vasopressin has been shown to be comparable to intravenous administration during CPR in terms of plasma levels, haemodynamic response and rate of successful resuscitation.
It should be noted that in all of the above studies, exogenous arginine vasopressin was administered. A potential limitation of these studies is that pigs possess lysine vasopressin receptors while humans have arginine vasopressin receptors. It is postulated therefore that the cardiovascular response to exogenous arginine vasopressin may be greater in humans than in pigs.73,75
To date the human literature on the use of vasopressin for advanced cardiac life support (ACLS) is limited .
In a study of 10 patients already deemed non Šsalvagable after prolonged conventional ACLS (mean duration 39.6+/-16.5 min), coronary perfusion pressure was measured 5 minutes after a bolus dose of adrenaline 1mg, followed by vasopressin 1U/kg.No improvement in coronary perfusion pressure occurred following adrenaline. However in four patients, vasopressin produced a mean increase in coronary perfusion pressure of 28.2mmHg, with the peak increase occurring between 15 seconds and 4 minutes after drug administration.79
In a randomised double-blind study of 40 patients receiving either adrenaline 1mg or vasopressin 40U for out- of -hospital ventricular fibrillation, twice as many patients in the vasopressin group (7 vs. 14 patients) survived to hospital admission (NS). At 24 hours, 4 adrenaline- treated patients were alive vs. 12 vasopressin- treated patients (p<0.02).78However, in a randomised trial of 200 in-hospital cardiac arrests, vasopressin 40U was no more effective than adrenaline 1mg. 98 The authors of this study concluded that vasopressin could not be recommended for in- hospital cardiac arrest. Other authors have challenged this conclusion for the following reasons: Firstly, nearly 50% of the patients in this study had pulseless electrical activity, which has a very poor prognosis. Secondly , the mean time to study drug administration in the in-hospital study was about half that of the out-of-hospital study Šwhich may have masked the potential benefit from vasopressin suggested by the animal studies of prolonged CPR.99
The European Resuscitation Council is currently supporting a large Austrian study of vasopressin versus adrenaline for out of hospital cardiac arrest . This randomised, multicenter study of 1500 patients is due for completion later this year. Preliminary results from the first 450 cases have not revealed any adverse effects or complications associated with vasopressin use.80
In the latest ACLS guidelines of the American Heart Association, vasopressin (40U iv. as a single bolus) may be substituted for adrenaline in the treatment of cardiac arrest. The evidence Šbased classification of vasopressin is Class IIb (acceptable, with fair supporting evidence) .81
The outcome from hypovolaemic cardiac arrest remains dismal,82-84leading to some trauma units advocating withholding treatment from patients who arrest from blunt trauma prior to arrival in hospital. CPR is unlikely to be effective in an exsanguinated patient and although adrenaline is advocated as part of ACLS for hypovolaemic cardiac arrest,85,86its efficacy is unknown. In addition, after prolonged hypovolaemic shock some patients will die from irreversible shock after initially responding to volume replacement and catecholamines. Irreversible shock ensues when there is a progressive reduction in vascular responsiveness to catecholamines, despite restoration of blood volume. Recent evidence suggests that vasopressin may improve survival from cardiac arrest occurring during hypovolaemia and may also reverse ŅirreversibleÓ shock due to prolonged hypovolaemia.
The effect of vasopressin on survival after cardiac arrest during hypovolaemic shock was studied in 18 anaesthetised pigs.8735% of their blood volume was withdrawn and after 15 minutes VF was induced electrically. After 4 minutes of cardiac arrest, CPR was then performed for a further 4 minutes before a bolus dose of adrenaline 0.2mg/kg (n=7), vasopressin 0.8U/kg (n=7) or placebo(n=4) was administered. Defibrillation was attempted 2.5minutes later, followed by repeat drug doses if unsuccessful. All vasopressin Štreated pigs were successfully defibrillated, as were 6/7 adrenaline treated pigs. None of the placebo group could be defibrillated. However, one hour later all of the adrenaline and none of the vasopressin Štreated pigs had died (p<0.01). Although mean arterial pressure and coronary, cerebral, and adrenal blood flow were significantly higher in the adrenaline group at 5 minutes, by 30minutes they were all significantly lower than the vasopressin group. Renal blood flow was significantly higher in the vasopressin group at all times. Adrenaline treated animals had a lower arterial and mixed venous pH during the entire postresuscitation phase, possibly due to excess metabolism from §-adrenergic stimulation along with renal hypoperfusion. High dose adrenaline may also cause cardiac failure following CPR from hypovolaemic shock by critically increasing myocardial oxygen demand above supply, consistent with the results from other experimental models of CPR.71,88
The effect of vasopressin on intractable shock was studied in 7 dogs.17 This was induced by draining blood from the animals into a reservoir until a mean arterial pressure (MAP) of 40mmHg was reached. The height of the reservoir was then altered to maintain this MAP. After a variable period of time vasodilation occurred, indicated by the passive transfer of blood from the reservoir to the dogs. Severe hypotension persisted despite restoration of blood volume and noradrenaline infusion at 3ug/kg/min. However, within 5 minutes of vasopressin infusion at 1-4mU/kg/min, MAP increased from a mean of 39 to 128mmHg (p<0.01) and remained above 90mmHg for the 50 minute study period. As expected, vasopressin levels measured soon after the onset of hypotensive haemorrhage were markedly elevated (319+66 pg/ml), but had fallen to 29 +9 pg/ml before vasopressin administration (p<0.01).
Vasopressin has been successfully used in two case reports of refractory hypotension due to haemorrhage.17 The first patient had prolonged severe hypotension (systolic arterial pressure (SAP) ~50mmHg for > 1 hour) from variceal bleeding that was refractory to volume replacement, high dose noradrenaline and dopamine infusion. After 10 minutes of vasopressin infusion at 4uU/kg/min, their SAP was 160mmHg and the catecholamines had been ceased. In the second case, prolonged severe hypotension occurred after a gastric bleed in young adult with end-stage renal failure. This persisted despite transfusion to a CVP of 17mmHg and noradrenaline infusion, however after 10 minutes of vasopressin infusion at 1uU/kg/min their SAP rose from 70 to 130mmHg.
Vasopressin and sepsis
The characteristic haemodynamic disturbance caused by septic shock is generalised vasodilation and myocardial depression. Acceptable mean arterial pressures may be restored by catecholamine vasopressors, but critical reductions in regional blood flow (especially splanchnic) may occur.89,90However, in some patients with vasodilated septic shock the pressor response to catecholamines may be markedly reduced91,92while the response to vasopressin is markedly enhanced.31It was therefore hypothesised that a relative deficiency of endogenous vasopressin might contribute to this lack of vascular responsiveness.19Normally, sepsis is a potent stimulus for vasopressin release. In an animal model, massive endogenous vasopressin release occurred in response to infusion of E.coli.7Levels peaked within the first two hours then declined, but remained well above baseline up to12 hours later. The plasma vasopressin level produced was comparable to that seen in other severe shock states, such as hypotension due to haemorrhage. There is no animal data on the effect of prolonged septic shock on vasopressin levels. However, in a study of 19 humans with vasodilatory septic shock who were receiving catecholamines, plasma levels of vasopressin were significantly lower than in 12 patients who were in cardiogenic shock (3.1 vs. 22.7pg/ml, p<0.01).17These levels were thought to be inappropriately low for the level of hypotension seen in these patients (mean arterial pressures 92/52mmHg). Vasopressin was then infused at 0.04U/min in 10 patients. Within 15 minutes, the mean systolic arterial pressure increased to 146mmHg (p<0.01) due to a 79% increase in systemic vascular resistance. In 6 patients, catecholamine therapy could be ceased. In these 6 patients, cessation of vasopressin infusion resulted in hypotension within a few minutes (SAP 126 to 83mmHg, p<0.01). Reinstituting a lower-dose vasopressin infusion (0.01U/min) resulted in a further sustained improvement in blood pressure (83 to 115mmHg, p<0.01).
Vasopressin 0.04U/min was compared with placebo in 10 patients with vasodilatory septic shock in a double Šblind study (n=5 each group).93Study criteria were septic patients who required catecholamine vasopressors to maintain a MAP of 70mmHg despite a cardiac index of > 2.5l/min/m2 and a PCWP of ³12mmHg. Vasopressin infusion resulted in an increase in systolic arterial pressure (98 to 125mmHg, p<0.008) due to peripheral vasoconstriction (SVR 878 to 1,190 dyne/s/cm-5). All of the vasopressin group were able to be completely weaned from catecholamines, and all patients survived the 24 hour study period. Two patients in the placebo group died from refractory hypotension (MAP < 50mmHg). In a review of 50 patients with septic shock, vasopressin use lead increased MAP (18%), reduced cardiac index (11%), increased urine output (79%) and reduced catecholamine requirements. 100 Pulmonary artery pressures were not changed. Doses higher than 0.04U/min were not associated with increased effectiveness and may have been associated with more side effects.
Excessive vasodilation can occur soon after initiating cardiopulmonary bypass (CPB) due to the effects of haemodilution, cardioplegia and chronic ACE-inhibitor therapy.21In a patient who developed hypotension during CPB that was refractory to boluses of phenylephrine and noradrenaline infusion, 1 unit of vasopressin effectively restored vascular tone.94
Cardiopulmonary bypass induces an inflammatory response that causes similar haemodynamic disturbances to sepsis. Characteristic features are hypotension due to peripheral vasodilation, diminished vascular responsiveness to catecholamines and a high cardiac output. In a study of 145 general cardiac cases, postbypass vasodilatory hypotension occurred in 11 cases (8%). Plasma vasopressin levels were significantly lower in the vasodilated patients than in 9 patients who had cardiogenic hypotension following CPB (12.0 vs. 29.3pg/ml, p < 0.04). 21In a retrospective review from the same study, 26 heart transplant and 16 patients on left ventricular assist devices received vasopressin (commencing at 0.1U/min) for vascular support. Infusions were commenced on bypass up to several hours after weaning and were continued for up to 6 days. Vasopressin administration produced significant increases in MAP and vascular resistance along with significant reductions in noradrenaline support. The haemodynamic response to vasopressin was most pronounced in the most severely hypotensive group of patients. After catecholamine support had been successfully withdrawn, vasopressin was slowly tapered to 0.02U/min.,then discontinued.
Vasopressin can correct vasodilatory shock following CPB even in non-vasopressin deficient patients. In a randomised, controlled trial of 10 patients undergoing insertion of a left ventricular assist device who had post bypass vasodilatory shock, 5 patients received either vasopressin at 0.1U/min or placebo.20Vaodilatory shock was defined as a MAP of < 70mmHg, a cardiac index of > 2.5 L/min/m2 and noradrenaline dependence. Vasopressin produced a rapid increase in mean arterial pressure (57 + 4 to 84 + 2, p < 0.01) and SVR (813 + 113 to 1188 + 87 dyne/s/cm-5). Within 15 minutes of commencing the vasopressin infusion, 4 patients could be completely weaned from noradrenaline. Although not significant, patients with low plasma vasopressin levels were more hypotensive and had a greater pressor response to vasopressin than patients with higher levels.
Vasopressin has also been successfully used in a study of 11 infants and children with vasodilatory shock post-CPB that was refractory to catecholamines.101 The clinical response was greatest in those children that had adequate cardiac function postoperatively. Doses used ranged from 0.0003-0.002U/kg/min.
Administration of vasopressin (10U followed by an infusion at 14, then 7U/h) produced a marked haemodynamic improvement in a patient who had cardiogenic shock and pulmonary oedema after prolonged CPB for a double-valve procedure -without affecting filling pressures. 95 Although the improvement in cardiac output may have been secondary to an increased coronary perfusion pressure, it is also possible that vasopressin produced a positive inotropic effect.
Although there are a number of serious reported side effects from vasopressin therapy for other clinical indications, there were few complications attributable to vasopressin in any of these studies reviewed, even after up to 6 days of vasopressin infusion. However, in a study of septic and post-CPB shock, vasopressin use was associated with significant increases in liver enzymes and total bilirubin concentrations and significant decreases in platelet counts.102The rise in liver enzymes may have been due reduced gastrointestinal perfusion , while the reduction in platelet count may have been due to vasopressin-induced platelet aggregation.103
There have been case reports of major complications produced by vasopressin in other clinical settings.65,96 Cardiac complications have lead to fatalities and include myocardial ischaemia, myocardial infarction, ventricular arrhythmias (including ventricular tachycardia and asystole) and severe hypertension. Severe gastrointestinal tract ischaemia leading to bowel necrosis has been reported as have hyponatraemia, anaphylaxis, bronchospasm, urticaria, angioedema and rashes. Peripheral vasoconstriction leading to cutaneous gangrene has been reported in five cases, in only one of whom was there evidence of extravasation. Venous thrombosis and local irritation of the injection site may also occur.
One explanation for the absence of side effects from vasopressin use during shock may simply be that a relatively small total number of patients have been studied. However, there are other possible explanations. The dose of vasopressin used in shock states was relatively low compared to that used in other indications. For example, the vasopressin doses typically used post CPB were ² 0.1U/min, while the dose used for variceal bleeding is 0.1-0.4U/min.97 It is also possible that because shocked patients may have inappropriately low endogenous vasopressin levels, fewer side effects might occur from exogenous vasopressin administration.
Vasopressin is an intriguing new therapy for a variety of vasodilatory shock states that promises to be a major advance in resuscitation.
Endogenous vasopressin release is an important pressor mechanism in the physiological response to shock, and inadequate vasopressin levels will exacerbate hypotension. Although vasopressin has some similar vascular actions to the catecholamines, it may uniquely also reverse some of the pathological vasodilatory processes produced by shock.
While there is relatively limited human data on the use of vasopressin in shock, the evidence available does confirm some of the promising findings from animal studies.
During ACLS for ventricular fibrillation, vasopressin produces more favourable and sustained blood flow diversion from non-critical to critical organ beds (especially brain) than does adrenaline, and may improve survival in humans. Should these findings be confirmed by large studies in progress, vasopressin may potentially supplant adrenaline as a first-line therapy.
Although human evidence is lacking, vasopressin may be a useful therapy for hypovolaemic cardiac arrest. There is also limited, though tantalising evidence that vasopressin may reverse ŅirreversibleÓ hypovolaemic shock.
Vasopressin is effective in reversing hypotension due to septic shock although there is as yet no data on outcome or on safety when compared with the use of the catecholamines.
Following cardiopulmonary bypass, vasodilatation that is relatively refractory to catecholamines may be reversed by vasopressin. From the limited evidence available, vasopressin does not appear toproduce adverse cardiac effects in this particularly vulnerable group of patients. Further studies are needed on how vasopressin might best be used for this indication. As well as further clinical studies on efficacy and safety, there is a need for pharmacodynamic and pharmacokinetic information on the use of vasopressin in shock.
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