Decatecholaminization in septic shock

A subset of patients from the 2008 Vasopressin and Septic Shock Trial (VASST) trial had invasive haemodynamic monitoring measurements from pulmonary artery catheters. These data have now been analysed, revealing that vasopressin was associated with a lower heart rate compared with norepinephrine (noradrenaline) alone, without significant difference in cardiac index or stroke volume index. However, there was significantly greater use of inotropic drugs in the vasopressin group compared with the norepinephrine group.

Tachycardia and high quantities of catecholamine infusion are both associated with mortality in sepsis. The authors discuss:

“The idea of decatecholaminization, reducing both endogenous and exogenous adrenergic stimulation, is now believed to be an important treatment strategy, and the use of beta-blockers in septic shock is being considered. The early use of vasopressin or specific V1a receptor agonists in early septic shock may be another possible treatment.”

This interesting post-hoc analysis may help further define the patients in whom vasopressin is to be considered, by those clinicians who are using it in septic shock. For those that aren’t, I wouldn’t worry about it.

The cardiopulmonary effects of vasopressin compared with norepinephrine in septic shock
Chest. 2012 Sep;142(3):593-605
Click for abstract

Nitrate bolus in acute heart failure

Despite intravenous nitrate boluses being used in original studies demonstrating benefit in acute heart failure^1,2, I regularly meet reluctance from both physicians and nurses in the emergency department to give them.

Their resistance seems to be based on a concern for inducing hypotension, and they prefer to ‘titrate up’ an infusion.

iv nitrate options include nitroglycerin (GTN), and isosorbide dinitrate (ISDN). Studies have used ISDN 4mg every 4 mins, ISDN 3mg every 5 mins, and GTN 2mg every 3 mins³.

There are a number of reasons to avoid starting with a low rate infusion in a sick heart failure patient.

Matthew Reed highlighted cannula size as an important factor⁴:

If a GTN infusion is commenced at a rate of 1 ml/h, a critically unwell patient with a large cannula—for example, a grey cannula (16G) — will have to wait over 6 min for the drug to enter the body. This compares with 1.5 min for a pink cannula (20G) at the same infusion rate. If a large-diameter cannula is chosen for these patients, then a fast initial infusion rate should also be chosen to ensure that the GTN begins to act quickly.

Alistair Steel subsequently pointed out further reasons to avoid slow infusions⁵:

(1) mechanical slack within an infusion device may mean an infusion set at 1 ml/h will take many minutes for the driver to contact and advance the syringe plunger. For this reason, infusions should be purged before patient connection.

(2) the pharmacokinetics of the drug should be considered. At low infusion rates it will take significant time for a steady state to be achieved (a drug such as GTN, with a half-life of 2 min, would require 10 min to achieve steady state). For clinical effects to be seen quickly, a bolus should be given before commencing infusions.

(3) the use of 1 ml/h infusions (8 µg/min using a 0.5% solution) may be excessively cautious – the British National Formulary recommends a therapeutic dose range from 10 to 200 µg/min. Furthermore, there is emerging evidence that, when used for decompensated heart failure, higher doses of GTN are associated with more favourable outcomes.

(4) at low infusion rates any obstruction in the intravenous system will take a proportionally longer time to become apparent, as it will take longer for the pressure to build up and trigger the syringe pump’s high pressure alarm..

Now a recent study confirms such a regimen can be used safely in the elderly. ISDN 3mg bolus treatment was not associated with higher rates of hypotension in the elderly population treated for heart failure in the emergency department. Despite a small study and a retrospective design, this lends support to the practice of iv bolus nitrate therapy for acute heart failure, even in the elderly.

1. Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema
Lancet. 1998 Feb 7;351(9100):389-93

2. High-doses intravenous isosorbide dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema
J Am Coll Cardiol. 2000 Sep;36(3):832-7 Free Full Text

3. Managing acute pulmonary oedema with high or standard dose nitrate
Emerg Med J. 2009 May;26(5):357-8

4. Administering a glyceryl trinitrate infusion: big is not always best
Emerg Med J 2007;24:423-424

5. Administering a glyceryl trinitrate infusion: faster is better than slower
Emerg Med J. 2008 Jan;25(1):60

6. Isosorbide dinitrate bolus for heart failure in elderly emergency patients: a retrospective study
Eur J Emerg Med. 2011 Oct;18(5):272-5

Phentolamine for neurogenic pulmonary oedema

A single case report might not be practice changing, but it’s helpful to know about this option:

A patient with acute intracerebral haemorrhage developed hyoxaemia due to neurogenic pulmonary oedema, accompanied by a labile blood pressure and elevated catecholamine levels.

Nicardipine and other antihypertensive agents including metoprolol, hydralazine, and labetalol were tried without benefit, and the patient continued to deteriorate.

Phentolamine was tried. The introduction, withdrawal, and reintroduction of phentolamine and the clinical status of the patient is described convincingly:

a phentolamine infusion was started at 0.17 mg/min and titrated for BP control. Over 6 h, the FIO2 requirements dropped precipitously, gas exchange improved, and the chest radiograph showed improvement of pulmonary edema. When the hospital supply of phentolamine was exhausted, the clinical status deteriorated rapidly. Within just 15 h of the discontinuation of phentolamine, the PaO2 fell from 166 mm Hg to 66 mm Hg, and FIO2 requirements rose from 60% to 100%. When the phentolamine supply was replenished and the infusion restarted, the same rapid improvement was observed and BP stabilized.

Phentolamine is a potent competitive antagonist at both alpha 1 and alpha 2 receptors . Phentolamine causes a reduction in peripheral resistance through blockade of alpha 1 receptors and possibly alpha 2 receptors on vascular smooth muscle.

Abstract
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. The cause is believed to be a surge of catecholamines that results in cardiopulmonary dysfunction. Although there are myriad case reports describing CNS events that are associated with this syndrome, few studies have identified specific treatment modalities. We present a case of NPE caused by an intracranial hemorrhage from a ruptured arteriovenous malformation. We uniquely document a rise and fall of serum catecholamine levels correlating with disease activity and a dramatic clinical response to IV phentolamine.

Neurogenic Pulmonary Edema: Successful Treatment With IV Phentolamine
Chest March 2012 vol. 141 no. 3 793-795

Dobutamine for severe heart failure – more harm than good?

A systematic review and meta-analysis of randomised controlled trials showed dobutamine is not associated with improved mortality in heart failure patients and in the case of severe heart failure there is some suggestion of increased mortality, although this did not reach statistical significance.

The authors do point out that the quality of the reports of the trials reviewed was suboptimal. However, they state:
It should be noted that the results of this study are in accord with large observational studies that have also suggested harm associated with use of dobutamine in patients with severe heart failure. Taken together, this evidence should cause clinicians to reconsider their use of dobutamine in patients with heart failure, particularly those most at risk of the adverse effects, those with underlying ischaemic heart disease.

PURPOSE: Dobutamine is recommended for patients with severe heart failure; however uncertainty exists as to its effect on mortality. This study aims to critically review the literature to evaluate whether dobutamine, compared with placebo or standard care, is associated with lower mortality and a range of secondary outcomes, in patients with severe heart failure.

METHODS: A systematic review and meta-analysis of randomised controlled trials was performed. PubMed, EMBASE, the Cochrane Central Trials Registry, the metaRegister of Controlled Trials and bibliographies of retrieved articles were searched. Randomised trials comparing dobutamine with placebo or standard care, in human, adult patients with severe heart failure, were included if they reported at least one outcome of interest. Data regarding trial validity, methodological processes and clinical outcomes were extracted, and a meta-analysis was performed.

RESULTS: Fourteen studies, with 673 participants, met the inclusion criteria and were included; 13 studies reported mortality. There was minimal heterogeneity (I (2) = 4.5%). The estimate of the odds ratio for mortality for patients with severe heart failure treated with dobutamine compared with standard care or placebo was 1.47 (95% confidence interval 0.98-2.21, p = 0.06).

CONCLUSIONS: This meta-analysis showed that dobutamine is not associated with improved mortality in patients with heart failure, and there is a suggestion of increased mortality associated with its use, although this did not reach the conventional level of statistical significance. Further research to define the role of dobutamine in treatment of severe heart failure should be a priority.

Dobutamine for patients with severe heart failure- a systematic review and meta-analysis of randomised controlled trials
Intensive Care Med. 2012 Mar;38(3):359-67

Epinephrine in cardiac arrest reanalysed

A post hoc reanalysis was performed on a 2009 JAMA paper comparing patients randomised to receive or not receive prehospital drugs and iv access for cardiac arrest.

This was done to evaulate the effect of adrenaline/epinephrine. The reason for the reanalysis was that in the original intention-to-treat analysis, some of the following issues may have influenced the results:

• Some patients randomised to adrenaline never received it as they had ROSC before the drug could be given, thus yielding a selection bias with the most easily resuscitated patients in the post hoc no-adrenaline group
• At least 1 of 5 patients randomised to receive IV access and drugs did not receive adrenaline as it was regarded futile or it was impossible to gain intravenous access
• 1 of 10 patients randomised to not receive drugs received adrenaline after they had regained spontaneous circulation for > 5 min.

The purpose of this post hoc analysis on the RCT data was to compare outcomes for patients actually receiving adrenaline to those not receiving adrenaline.

The actual use of adrenaline was associated with increased short-term survival, but with 48% less survival to hospital discharge. The improved survival to hospital admission is consistent with the results of a recent Australia study, and the negative association with longer term survival is similar to a multivariate analysis of observational Swedish registry data where patients receiving adrenaline were 57% less likely to be alive after one month.

Yet more evidence that we haven’t found any drugs proven to improve survival in cardiac arrest. At least not until the human studies on sodium nitroprusside come out?

I bet some of you are still going to be giving the epi exactly every four minutes though.

**Update: see Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest – more prospective data from Japan, this time showing epinephrine improves prehospital ROSC, but decreases chance of survival and good functional outcomes 1 month after the event.**

PURPOSE OF THE STUDY: IV line insertion and drugs did not affect long-term survival in an out-of-hospital cardiac arrest (OHCA) randomized clinical trial (RCT). In a previous large registry study adrenaline was negatively associated with survival from OHCA. The present post hoc analysis on the RCT data compares outcomes for patients actually receiving adrenaline to those not receiving adrenaline.

MATERIALS AND METHODS: : Patients from a RCT performed May 2003 to April 2008 were included. Three patients from the original intention-to-treat analysis were excluded due to insufficient documentation of adrenaline administration. Quality of cardiopulmonary resuscitation (CPR) and clinical outcomes were compared.

RESULTS: Clinical characteristics were similar and CPR quality comparable and within guideline recommendations for 367 patients receiving adrenaline and 481 patients not receiving adrenaline. Odds ratio (OR) for being admitted to hospital, being discharged from hospital and surviving with favourable neurological outcome for the adrenaline vs. no-adrenaline group was 2.5 (CI 1.9, 3.4), 0.5 (CI 0.3, 0.8) and 0.4 (CI 0.2, 0.7), respectively. Ventricular fibrillation, response interval, witnessed arrest, gender, age and endotracheal intubation were confounders in multivariate logistic regression analysis. OR for survival for adrenaline vs. no-adrenaline adjusted for confounders was 0.52 (95% CI: 0.29, 0.92).

CONCLUSION: Receiving adrenaline was associated with improved short-term survival, but decreased survival to hospital discharge and survival with favourable neurological outcome after OHCA. This post hoc survival analysis is in contrast to the previous intention-to-treat analysis of the same data, but agrees with previous non-randomized registry data. This shows limitations of non-randomized or non-intention-to-treat analyses.

Outcome when adrenaline (epinephrine) was actually given vs. not given – post hoc analysis of a randomized clinical trial
Resuscitation. 2012 Mar;83(3):327-32

The REAL Shocked Patient

I promised to put some summary notes on the site for those who attended my talk on ‘The REAL Shocked Patient’ for the Australian College of Ambulance Professionals on Tuesday 21st February 2012, so here they are:

Shocked patients are important – they comprise most of the ‘talk and die’ caseload that preoccupies pub conversations between emergency physicians

It’s easy to mistake these patients as less sick than, say, hypoxic ones, but oxygen delivery to the tissues doesn’t just depend on oxygen!

Here’s a dead wombat – someone in the audience knew a worrying amount about wombat anuses.

The 4 Hs and 4 Ts aren’t a very cognitively practical mnemonic for the causes of PEA arrest (which is an extreme form of hypotension)

I prefer the ’3 plus 3′ rule, which breaks down the causes into three – volume, pump, and obstruction. Obstruction is further broken down into three causes, being tension pneumothorax, cardiac tamponade, and pulmonary embolism:

Let’s look at some cases of shock caused by volume deficit, pump falure, or one of the three causes of obstruction to the circulation:

 

Case 1: The hypotensive motorcyclist
His low back pain suggested pelvic fracture
Think of ‘blood on the floor and four more’ (chest, abdomen, pelvis/retroperitoneum, long bones) and consider non-bleeding causes such as neurogenic (spinal injury), tension pneumothorax, cardiac tamponade, and finally medical causes/iatrogenic (drug) causes.
Don’t underestimate the importance of pelvis and limb splinting as a haemorrhage control technique in blunt trauma
Ultrasound in flight made thoracic or abdominal bleeding very unlikely, and ruled out tamponade and pneumothorax

Although he was hypotensive, no fluids were given, as he was mentating normally and peripherally well perfused, with a radial pulse. If we gave fluid, we would titrate to the presence of a radial pulse (in blunt trauma) but we don’t want to ‘pop the clot’ by elevating the BP, or make him less able to form effective clots by diluting his blood with crystalloid.

Mortality in trauma sharply rises with systolic BP below 105-110, so recalibrate your definition of hypotension in terms of when you might be concerned, and which patients may benefit from triage to a trauma centre.

 

Case 2: The child crushed by a wall
Caution regarding lower limb infusions in patients with abdominal / pelvic injuries – the fluid may not get to the heart.

The classification of shock into four classes is crap. Never let the absence of a tachycardia reassure you.

Intraosseous is awesome, and EZ-IO has the best track record by far.

 

Case 3: The boy stabbed in the upper thigh
In penetrating limb trauma, prehospital options include pressure, elevation, tourniquet, and haemostatic dressings. Foley catheters have been used successfully in transition zones such as the neck or groin.

 

Case 4: Haematemesis
Should we apply the same principles of permissive hypotension to patients with ‘medical’ bleeding?
The Trendelenburg position doesn’t make a lot of sense – no need to head down the patient, although the act of elevating the legs may ‘autoinfuse’ a bolus of blood to the core circulation, and is recommended by some bodies as a first aid manoeuvre for hypotensive patients in the field prior to iv fluids.

 

Case 5: The overdose patient with a low blood pressure but otherwise fine.
When don’t I Worry about hypotension? When the patient is:

• With it
• Warm peripherally
• Weeing
• and (in hospital) Without a raised lactate

Case 6: Two cases of pump failure: STEMI and complete heart block
Adrenaline infusions can be simply made with a 1mg 1:10000 minijet diluted in a litre of saline and dripped through a peripheral line titrated to BP / HR / mentation / pulses.
In complete heart block (or other bradycardias) with hypotension, percussion pacing is an option of you don’t have access to transcutaneous or transvenous pacing. If you get capture, it’s as effective in terms of stroke volume as a pacing wire.

 

Case 7: Obstructive shock – tamponade cases
…with resolution of hypotension after drainage by emergency physicians who identified the tamponade on ultrasound, even though they didn’t suspect it clinically. It can be a surprise!

 

Case 8: Obstructive shock – tension pneumothorax
Patients are often agitated and won’t lie flat. They may complain of ‘tight’ breathing. Crackles and/or wheezes may be heard. The classic description of deviated trachea, absent breath sounds, and hyperresonance are the exception, not the rule. Be suspicious and always palpate for subcutaneous emphysema.
Don’t assume a needle decompression will work – there is debate about the best site but in some adults a standard needle won’t reach the pleural space. If you need to place more than one needle, go for it. As physicians, we do thoracostomies to ensure we’ve hit the spot.

 

Case 9: Obstructive shock – pulmonary embolism
A tough one prehospital, as the hypotensive ones need fibrinolysis. Fluid may help the hypotension but too much can overdistend the right ventricle which can then impair left ventricular filling, and worsen the patient’s circulatory state. Once again, ultrasound may be invaluable in highlighting PE as a possible cause for shock.

 

Case 10: Penetrating trauma to the ‘box’ – chest and upper abdomen.
If these patients arrest due to tamponade, early (< 10 minutes) clamshell thoracotomy can be life saving, which means it may need to be done pre-hospital by a HEMS physician to provide a chance of survival. Be on the look out for these and if in doubt activate a medical team (in New South Wales). Like with tension pneumothorax, these patients may be extremely agitated as a manifestation of their shock.

 

Case 11: Confused elderly male with pyrexia and smelly urine who appears ostensibly ‘normotensive’
…but how many 82 year olds do you know with a BP of 110/57? His acute confusion may be a manifestation of shock and he needs aggressive evaluation in hospital including a lactate measurement. Don’t be afraid to give this guy fluids in the field – you can make a big difference here.

Here are five of the myths I promised to expose:

So…shocked patients can talk and die. Don’t let that happen. Shocked patients can be normotensive, and hypotensive patients might not be shocked. Have a plan for how you might evaluate the 3+3 causes in your setting and what you can use from your medication and equipment list to manage volume, pump, and obstruction issues. You will save many lives if you become a serious shock detective.

Vasopressin – what it does and doesn’t do

The current Surviving Sepsis campaign guidelines recommend that vasopressin should not be administered as the initial vasopressor in septic shock, and that vasopressin at constant dosage of 0.03 units/min may be added to norepinephrine with anticipation of an effect equivalent to that of norepinephrine alone. European intensivists conducted a systematic review to determine vasopressin’s risks and benefits in vasodilatory shock. There was no demonstrated survival benefit but its use is associated with a significant reduction in norepinephrine requirement.

Interestingly, the authors point out: ‘Low-dose vasopressin may help to restore blood pressure in patients with hypotension refractory to catecholamines, and may favor pulmonary vasodilation and increase glomerular filtration rate and plasma cortisol levels’.

My take home: consider its use if an apparent vasodilatory shock state is refractory to catecholamines, but don’t stress if you don’t have access to it (or it will complicate practical aspects of organising resuscitation and transfer), since there’s still no clear evidence for outcome benefit.

OBJECTIVE:
To examine the benefits and risks of vasopressin or its analog terlipressin for patients with vasodilatory shock.

DATA SOURCE:
We searched the CENTRAL, MEDLINE, EMBASE, and LILACS databases (up to March 2011) as well as reference lists of articles and proceedings of major meetings; we also contacted trial authors. We considered randomized and quasirandomized trials of vasopressin or terlipressin versus placebo or supportive treatment in adult and pediatric patients with vasodilatory shock. The primary outcome for this review was short-term all-cause mortality.

STUDY SELECTION:
We identified 10 randomized trials (1,134 patients). Six studies were considered for the main analysis on mortality in adults.

DATA EXTRACTION AND SYNTHESIS:
The crude short-term mortality was 206 of 512 (40.2%) in vasopressin/terlipressin-treated patients and 198 of 461 (42.9%) in controls [six trials, risk ratio (RR) = 0.91; 95% confidence interval (CI) 0.79-1.05; P = 0.21; I (2) = 0%]. There were 49 of 463 (10.6%) patients with serious adverse events in the vasopressin/terlipressin arm and 51 of 431 (11.8%) in the control arm (four trials, RR = 0.90; 95% CI 0.49-1.67; P = 0.75; I (2) = 26%). Metaregression analysis showed negative correlation between vasopressin dose and norepinephrine dose (P = 0.03).

CONCLUSIONS:
Overall, use of vasopressin or terlipressin did not produce any survival benefit in the short term in patients with vasodilatory shock. Physicians may value the sparing effects of vasopressin/terlipressin on norepinephrine requirement given its apparent safe profile.

Vasopressin for treatment of vasodilatory shock: an ESICM systematic review and meta-analysis
Intensive Care Med. 2012 Jan;38(1):9-19

Circulatory support in cardiogenic shock

An editorial¹ reviewing options for circulatory support in patients with cardiogenic shock argues that traditional inotrope therapy may be replaced by newer alternatives that have a less detrimental effect on myocardial oxygen demand.

Newer inotropic agents include levosimendan, istaroxime, and omecamtiv mecarbil. Mechanical therapies include intra-aortic balloon pumps (IABP), ventricular assist devices (VAD), and extracorporeal membrane oxygenation (ECMO).

Levosimendan is an inodilator, with the following characteristics:

• stabilises the myocardial calcium-troponin C complex
• activates adenosine triphosphate (ATP)-sensitive potassium channels in vascular smooth muscle and cardiac mitochondria,
• acts as a traditional phosphodiesterase inhibitor at higher doses
• improved cardiac output and a reduction in filling pressures compared with dobutamine
• may also improve diastolic function by increasing relaxation rate
• modulates the neuroendocrine response to heart failure by reducing brain natriuretic peptide levels
• has anti-apoptotic and anti-inflammatory effects
• renal function may also improve
• is associated with a similar risk of ventricular arrhythmias to dobutamine
• increases risk of new onset atrial fibrillation
• has conflicting literature surrounding mortality
• has shown a lack of consistent outcome benefits in studies
• may be useful in postmyocardial infarction cardiac dysfunction and septic shock through increasing coronary flow and attenuating inflammatory activation, respectively².

Istaroxime, a novel inotrope with positive lusitropic (cardiac relaxant) effects³:

• is an inhibitor of the sodium-potassium-ATPase (resulting, like digoxin, in elevated intracellular calcium) with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA)
• provides a dose-dependant increase in cardiac output without significant change in heart rate or arrhythmia
• in one study reducesd pulmonary capillary wedge pressure, increased systolic blood pressure, and reduced heart rate and left ventricular end-diastolic volume
• requires further clinical evaluation.

Omecamtiv mecarbil is a cardiac myosin activator. This new drug:

• improves myocardial contraction by increasing the hydrolysis of ATP by myosin ATPase
• this produces the power stroke between actin and myosin and subsequent shortening of sarcomere length
• in phase-2a studies in patients with systolic heart failure it demonstrated improved stroke volume without an increase in heart rate, although cardiac ischaemia emerged at high plasma concentrations^4,5.

1. Do inotropes really have a future?
Anaesthesia. 2011 Nov;66(11):972-6.

2. Inotropes in cardiac patients: update 2011
Curr Opin Crit Care. 2010 Oct;16(5):432-41
Abstract

3. Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output.
Discov Med. 2011 Aug;12(63):141-51 Free Full Text
Abstract

4. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study
Lancet. 2011 Aug 20;378(9792):667-75
Abstract

5. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial
Lancet. 2011 Aug 20;378(9792):676-83
Abstract

Why I don’t give vasopressors in sepsis

It’s become popular to use the term ‘vasopressors’ or just ‘pressors’ when noradrenaline/norepinephrine or even (in some places still) dopamine are given. I have resisted this trend and continue to use the term ‘vasoactive’ drugs, on the basis that the effects they produce (and that we may desire) are not limited to a pure alpha adrenergic effect on vascular tone, but they have effects on heart rate and contractility too (as well as preload through venous effects). If you don’t believe me about noradrenaline/norepinephrine, then check out one of my favourite critical care papers of all time: the CAT study.

There are of course real pressors out there – phenylephrine acts on alpha receptors, as does methoxamine. Metaraminol predominantly acts on alpha receptors but does also cause some release of noradrenaline/norepinephrine.

Why is this important? All these drugs will fix hypotension, right? Yes, they should. However should blood pressure be our main treatment goal? What we’re really interested in is organ perfusion, which depends on regional blood flow to vital organs. It’s possible that a drug could fix the measured blood pressure and give a nice ‘macroscopic’ number, while at the same time reducing cardiac output and adversely affecting regional blood flow to organs through local vasoconstrictive effects. My view is that this is more likely with pure ‘pressors’ (like phenylephrine), which is why I avoid them in septic shock and opt for catecholamine infusions (noradrenaline/norepinephrine).

This is important in my practice setting of retrieval medicine, where, prior to interfacility transport, physicians might sometimes be tempted to ‘push pressors’ peripherally rather than insert a central venous catheter and commence a catecholamine infusion. While the former approach might be more expeditious and make the vital signs chart look pretty, one wonders about what effect this is having on tissue oxygen delivery.

A fascinating review of papers on pressor physiology¹ suggests these agents have the following effects:

• conflicting data on changes in myocardial perfusion
• increase both left and right heart afterload
• decrease venous compliance with the potential to increase venous return although the impact of this on cardiac output is controversial
• controversial effect on cerebral bloodflow
• decrease bloodflow to the kidneys
• adverse affects on gastrointestinal tract bloodflow

abstract¹
Phenylephrine and methoxamine are direct-acting, predominantly α(1) adrenergic receptor (AR) agonists. To better understand their physiologic effects, we screened 463 articles on the basis of PubMed searches of “methoxamine” and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Both methoxamine and phenylephrine increase cardiac afterload via several mechanisms, including increased vascular resistance, decreased vascular compliance, and disadvantageous alterations in the pressure waveforms produced by the pulsatile heart. Although pure α(1) agonists increase arterial blood pressure, neither animal nor human studies have ever shown pure α(1)-agonism to produce a favorable change in myocardial energetics because of the resultant increase in myocardial workload. Furthermore, the cost of increased blood pressure after pure α(1)-agonism is almost invariably decreased cardiac output, likely due to increases in venous resistance. The venous system contains α(1) ARs, and though stimulation of α(1) ARs decreases capacitance and may transiently increase venous return, this gain may be offset by changes in afterload, venous compliance, and venous resistance. Data on the effects of α(1) stimulation in the central nervous system show conflicting changes, while experimental animal data suggest that renal blood flow is reduced by α(1)-agonists, and both animal and human data suggest that gastrointestinal perfusion may be reduced by α(1) tone.

A review of clinical articles² reveals few evidence-based indications for true pressors. Possible situations where they may be of benefit include intraoperative hypotension, aortic stenosis, during cyanotic episodes in Tetralogy of Fallot, and some obstetric situations. In the setting of sepis, phenylephrine has been compared with noradrenaline in which an initial pilot study found a statistically significant reduction in creatinine clearance and increase in arterial lactate after initiating the phenylephrine infusion. However a subsequent randomised controlled comparison of phenylephrine with noradrenaline/norepinephrine did not show differences in cardiopulmonary performance, global oxygen transport, or regional hemodynamics, although there were only 16 patients in each group³.

abstract²
Phenylephrine is a direct-acting, predominantly α(1) adrenergic receptor agonist used by anesthesiologists and intensivists to treat hypotension. A variety of physiologic studies suggest that α-agonists increase cardiac afterload, reduce venous compliance, and reduce renal bloodflow. The effects on gastrointestinal and cerebral perfusion are controversial. To better understand the effects of phenylephrine in a variety of clinical settings, we screened 463 articles on the basis of PubMed searches of “methoxamine,” a long-acting α agonist, and “phenylephrine” (limited to human, randomized studies published in English), as well as citations found therein. Relevant articles, as well as those discovered in the peer-review process, were incorporated into this review. Phenylephrine has been studied as an antihypotensive drug in patients with severe aortic stenosis, as a treatment for decompensated tetralogy of Fallot and hypoxemia during 1-lung ventilation, as well as for the treatment of septic shock, traumatic brain injury, vasospasm status-postsubarachnoid hemorrhage, and hypotension during cesarean delivery. In specific instances (critical aortic stenosis, tetralogy of Fallot, hypotension during cesarean delivery) in which the regional effects of phenylephrine (e.g., decreased heart rate, favorable alterations in Q(p):Q(s) ratio, improved fetal oxygen supply:demand ratio) outweigh its global effects (e.g., decreased cardiac output), phenylephrine may be a rational pharmacologic choice. In pathophysiologic states in which no regional advantages are gained by using an α(1) agonist, alternative vasopressors should be sought.

These review articles reinforce my own bias against the use of pure pressors in septic shock, although clearly more clinical research is needed. I am inclined to agree with the reviewers’ concluding statement:

…in all clinical settings, phenylephrine reduces cardiac output, and in most clinical settings has been shown to significantly increase LV afterload. Thus, only in instances in which its regional effects are thought to outweigh its global effects should phenylephrine be used for the treatment of hypotension.

1. The physiologic implications of isolated alpha(1) adrenergic stimulation
Anesth Analg. 2011 Aug;113(2):284-96

2. The clinical implications of isolated alpha(1) adrenergic stimulation
Anesth Analg. 2011 Aug;113(2):297-304

3. Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial
Crit Care. 2008;12(6):R143
Full Text available here

Still no cardiac arrest survival benefit from epinephrine?

A double blind randomised controlled trial showed significantly better rates of return of spontaneous circulation and hospital admission with the use of adrenaline (epinephrine) compared with placebo. This effect was observed with both shockable and non-shockable initial cardiac arrest rhythms. There was no statistically significant difference in the primary outcome of survival to hospital discharge.

Interesting but unfortunate political factors appear to have prevented recruitment to the required numbers of patients for this study so it is underpowered for its primary outcome of survival to hospital discharge, which in the adrenaline group was double that in the placebo group, although this did not reach statistical significance. What was supposed to be a multi-centre study became a single centre one and it was not possible to continue as the study drugs reached their expiry date and no additional funding was available.

So do ROSC and survival to admission matter? The authors make the following point:

While not the primary outcome of our study, ROSC is an increasingly important clinical endpoint as the influence of post resuscitation care interventions (i.e.: therapeutic hypothermia, managing underlying cause, organ perfusion and oxygenation) on survival to hospital discharge are recognised.

Optimum dose and timing of adrenaline remain unknown, along with whether it impacts on long-term outcomes.

BACKGROUND: There is little evidence from clinical trials that the use of adrenaline (epinephrine) in treating cardiac arrest improves survival, despite adrenaline being considered standard of care for many decades. The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest.

METHODS: We conducted a double blind randomised placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest. Identical study vials containing either adrenaline 1:1000 or placebo (sodium chloride 0.9%) were prepared. Patients were randomly allocated to receive 1ml aliquots of the trial drug according to current advanced life support guidelines. Outcomes assessed included survival to hospital discharge (primary outcome), pre-hospital return of spontaneous circulation (ROSC) and neurological outcome (Cerebral Performance Category Score – CPC).

RESULTS: A total of 4103 cardiac arrests were screened during the study period of which 601 underwent randomisation. Documentation was available for a total of 534 patients: 262 in the placebo group and 272 in the adrenaline group. Groups were well matched for baseline characteristics including age, gender and receiving bystander CPR. ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR=3.4; 95% CI 2.0-5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR=2.2; 95% CI 0.7-6.3). All but two patients (both in the adrenaline group) had a CPC score of 1-2.

CONCLUSION: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.

Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomised double-blind placebo-controlled trial
Resuscitation. 2011 Sep;82(9):1138-43

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