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Three Part Question

In [adult patients presenting to the Emergency Department with sepsis resulting in persistent hypotension not responding to fluid replacement] is a [peripheral metaraminol infusion as effective as central noradrenaline infusion] for [maintaining a blood pressure capable of effective organ perfusion].

Clinical Scenario

A previously fit and well 36 year old male returns from a holiday to Greece 48 hours ago and presents to the Emergency Department complaining of headache, malaise and feeling generally unwell. While waiting to be seen, the patient’s headache rapidly worsens, he spikes a high temperature of 38.9 ̊C, becomes increasingly agitated and starts vomiting. He is taken to a resuscitation cubicle and has a heart rate of 135 bpm and blood pressure 71/45 mmHg. Examination of the patient reveals several small non blanching petechiae. You manage the patient as suspected meningitis and commence appropriate sepsis management. After 3 litres IV fluid the patient remains with a systolic blood pressure less than 80mmHg. The intensive care doctor informs you that they are trying to make a space available in the ITU for this patient but are struggling to step anyone down and the patient must remain in the resuscitation department. The resuscitation nurse asks you to prescribe more fluid. You wonder whether a peripheral metaraminol infusion would be more effective at increasing arterial pressure and maintaining organ perfusion.

Search Strategy

Ovid MEDLINE® 1946 to present
EMBASE® 1974 to present
CINAHL® 1981 to present
ProQuest® Database
Pubmed® Database
Cochrane Database
NICE evidence Database
College of Emergency Medicine

A grey literature search was performed via www.google.com, www.opengrey.eu and www.controlled-trials.com

([metaraminol.mp. or exp metaraminol] OR [aramine.mp. or exp aramine] OR [levicor.mp] AND [noradrenaline.mp. or exp norepinephrine] OR [adrenaline.mp. or exp epinephrine] AND [sepsis.mp or sepsis] OR [hypotension.mp or hypotension])

The references and citations of review articles were also searched for articles relevant to the three-part question.

Search Outcome

The MEDLINE search produced 35 papers

The EMBASE search produced 5 papers

The CINAHL search produced 4 papers

The ProQuest search produced 55 papers

The PubMed search produced 150 papers

The Cochrane database revealed one article of interest but I was unable to obtain bar a world-wide search and translation.

A NICE evidence search identified no additional relevant articles.

The college of emergency medicine website contained no relevant evidence or guidelines. The Australian, American, Canadian and New Zealand Colleges of emergency medicine were searched but contained no relevant evidence or guidelines.

Citations from articles of interest were also searched and revealed several new articles which appeared relevant to the three part question. However these all predated publication from 1964. For most articles I was unable to obtain an abstract, the abstract was in a foreign language and I was unable to obtain any articles in full via internet or library searches.

In total, 8 articles were identified that were relevant to the three part question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Natalini et al, 2005, Italy	10 patients admitted to a single Italian Medical and Surgical Intensive Care Unit who met following inclusion criteria: (a) diagnosis of septic shock (b) adequate fluid resuscitation and pulmonary artery occlusion pressure > 14mmHg (c) use of norepinephrine to maintain MAP > 65mmHg. Norepinephrine (N). Metaraminol (M)	Prospective Cohort Study. Level 2b	Detection of cardiac output > 30%	No significant difference demonstrated in stroke volume index (ml beatsˉ¹mˉ²) N (40±15) M (40±15) (p=0.991) and heart rate (beats minˉ¹) N (96±15) M (95±21) (p=0.863)	No randomisation of study drugs No blinding of physicians or patients (although does state this was considered unethical for the patient group being studied) Small patient numbers
			Haemodynamic variables	No significant difference demonstrated in global haemodynamic variables
			Drug doses	No relationship between N (0.30±0.28µg/Kgˉ¹minˉ¹) and M (2.5±1.7µg/Kgˉ¹minˉ¹) doses (R²=0.087)
			Patient acid base status	No difference in acid base status between N (-4.2+/-3.9) and M (-4.2+/-3.8) (p=0.919)
Hou et al, 2007, China	Single centre study. 98 patients with septic shock (using Hurford’s diagnostic criteria) were divided into three groups (A, B, C) according to highest infusion rate of metaraminol used (0.1-0.5, 0.6-1.0, >1.0) µg/Kgˉ¹ respectively	Retrospective Cohort Observational Study. Level 2b	1.Apache III 2.urine output (ml/h) 3.U-ALB (mg/L) 4.Uβ2-MG (mg/L) 5.BUN (mmol/L) 6.CRE (µmol/L)	No statistical significant differences in the changes of these renal function parameters with time among the three groups	No power calculation No control Group Unclear inclusion/exclusion criteria Retrospective reporting bias
Makowski and Misztal, 2010, UK	47 patients (25 female, 22 male) admitted to single centred surgical HDU who were started on peripheral metaraminol infusion (M)	Prospective Observational Study Level 3	Reason for starting M	Sepsis 34%, others 66%	Abstract only Poster presentation at the Lisbon International Anaesthesia Conference 2012 Small patient numbers
			Average infusion time	37.62hrs (range 1.5 – 144hrs)
			Central line insertion (%)	CVC’s inserted in 36% of patients
			Fluid balance (before/after M infusion) (mean±SD)	12 hours before infusion 2570.64±1198.01mls 12 hours after infusion 985±377.61mls (p=0.0001)
Udhoji et al, 1964, USA	12 patients with hypotension and clinical features of shock from varying aetiology. Levarterenol (noradrenaline, norepinephrine) Metaraminol or angiotensin were administered by intravenous infusion. 6 patients received angiotensin first followed by levarterenol or metaraminol. The other 6 patients received Levarterenol or Metaraminol followed by angiotensin.	Prospective Crossover Study. Level 2b	Cardiac Index	Cardiac indexes were lower in all cases during infusion of angiotensin vs levarterenol (1.7 vs 2.0 L/min/sq m) (p < 0.01) or metaraminol (1.8 vs 2.8 L/min/sq m) (p , 0.01)	Old Publication – less generalizable Small patient numbers (no power calculation) No blinding No description of randomisation technique Urine flow data difficult to interpret No washout period between different drugs No attempt to exclude confounding factors
			Urine Flow	In 10 of 12 patients urine flow was significantly reduced during angiotensin infusion compared to metaraminol or levarterenol.
Mills et al, 1960, USA	67 patients with shock from varying aetiology were given one or combination of Mephentermine, Metaraminol, Phenylephrine, Levarterenol, Epinephrine and Methoxamine. Patients were selected at random and treated by resident staff and faculty	Prospective Cohort Observation Study. Level 3	Shock due to MI	20 Patients. 13 survived. Survival rate in those with metaraminol exceeded previously reported with use of levarterenol	Old Publication – less generalizable No description of inclusion criteria Unclear methodology as how drugs were given, for how long, in which combination. Results section confusing as lists results from various other studies (both animal and human trials) No attempt at randomisation, blinding or exclusion of confounding factors
			Shock due to sepsis	9 Patients. 1 survived, 3 had satisfactory response to vasopressor therapy and were normotensive at death
			Shock due to haemorrhage	7 Patients. 2 survived. All those who failed to respond to metaraminol also failed to respond to levarterenol
			Shock due to various causes	31 Patients. 11 survived. All those who failed to respond to metaraminol were given levarterenol. Only one of those could reverse shock with eventual survival
Moyer at al, 1955, USA	20 patients in clinical shock of various aetiology. Ages ranged from 23 to 93 years old (average age 63 years). 14 males and 6 females. Given metaraminol infusion alone or in combination with noradrenaline.	Prospective cohort observational study. Level 3	Efficiacy of metaraminol infusion	19/20 patients had a satisfactory response within 8-10 minutes of infusion commencement. Duration of therapy lasted from 5 - 231.5 hours.	Old Publication – less generalizable No attempt at randomisation, blinding or exclusion of confounding factors Small patient numbers
			Administration doses	Metaraminol was approx. 1/20 to 1/25 as potent as norepinephrine during intravenous administration.
Weil, M.H. 1955, USA	42 patients included from 4 hospitals. All diagnosed with unequivocal shock of various aetiology. Age range 12 – 84 years (median age 61 years). 18 given metaraminol infusion alone, 24 were treated with other vasopressor agents and effects compared	Prospective multicentred cohort observational study Level 2b	Initial response to therapy	36 (86%) established prompt systolic BP of >= 100mmHg	Old Publication – less generalizable Small patient numbers No attempt at randomisation, blinding or exclusion of confounding factors
			Satisfactory maintenance to therapy	32 (76%) established sustained systolic BP of >= 100mmHg
			Mortality	16 (38%) survived to discharge
			Comparison with other agents	Norepinephrine gave a pressor response in 5 not responding to metaraminol – 4 of these subsequently died. Methoxamine achieved a less satisfactory response than metaraminol when given both intramuscular and intravenous in 5 patients. Phenylephrine also produced a weaker effect when compared in 2 patients.
Stechel et al, 1956, USA	250 patients admitted to a single centre in which the use of a vasopressor was indicated for shock of varied aetiology received metaraminol infusion. 42 cases reported in detail. (remaining 208 cases not included due to insufficient data concerning diagnosis or response to the drug)	Retrospective observational study. Level 3	Mortality	15 (36%) survived to hospital discharge. 27 (64%) died during this admission	Old Publication – less generalizable Small patient numbers No attempt at randomisation, blinding or exclusion of confounding factors
			Efficiacy of metaraminol infusion	No response to Blood pressure in 6 (14%) patients. Noradrenaline substituted in 12 patients who had no prompt response to metaraminol, all of whom died despite this.

Comment(s)

Natalini et al specifically focused on the comparison of noradrenaline and metaraminol as a vasopressor for the management of septic shock and revealed that there was no significant difference in patient’s cardiac output, haemodynamic variables or acid–base status. They also found that there was no relationship in the doses provided to achieve patient optimisation. Hou et al demonstrated that metaraminol infusion caused no statistical difference to renal function over time regardless of the infusion strength. Makowski et al conducted a small study which demonstrated that metaraminol can be given to good effect peripherally and potentially be used for long periods of time. The remaining studies demonstrated that metaraminol was an effective treatment for managing shock when compared with other vasopressor therapies, both in terms of drug efficacy and patient mortality. All of the studies were small retrospective or prospective cohort studies, with one small crossover trial, at which the level of evidence was not very strong. One of the studies was identified as a poster presentation at an International anaesthetic conference had only ever been published in abstract form, making appraisal of the study findings impossible. All the papers had low numbers of patients, there were no randomised trials and the outcomes were not always clear. Several of the publications were written in an unorthodox format which is likely a reflection of the period from which they were published, making appraisal of the data very difficult and applicability to modern medicine practice questionable. None of the papers used blinding or randomisation techniques, and only Natalini et al set out a detailed inclusion criteria to attempt to reduce confounding factors. Several of the selected papers were published over 50 years ago, making them no longer generalisable among modern medicine practice, while the Chinese patient group from Hou et al may not be reflective of a typical UK patient demographic.

Anecdotally, we know that peripheral metaraminol is used in UK practice and has many advocates, but this should arguably be tested in a randomised controlled trial with adult patients to compare peripheral metaraminol against alternative circulatory support strategies.

Clinical Bottom Line

There is limited evidence to support the use of peripheral metaraminol as vasopressor support in ED.

References

1. Natalini G , Schivalocchi V , Rosano A , et al. Norepinephrine and metaraminol in septic shock: a comparison of the hemodynamic affects. Intensive Care Med 2005;31:634–7.
2. Hou LC , Li SZ , Xiong LZ , et al. Effect of dopamine and metaraminol on the renal function of patients with septic shock. Chin Med J 2007;120:680–3.
3. Makowski A , Misztal B. Metaraminol peripheral infusion for the treatment of hypotension on surgical high dependency unit (SHDU) may reduce the need for excessive fluid administration in the post-operative population. Intensive Care Med 2010;36:0342–4642.
4. Udhoji, V.N. Weil, M.H. Circulatory Effects of Angiotensin, Levarterenol and Metaraminol in the Treatment of Shock. N Engl J Med 1964;270:501–5.
5. Mills LC , Voudoukis IJ , Moyer JH , et al. Treatment of Shock with Sympathicomimetic Drugs; Use of Metaraminol and Comparison with other Vasopressor Agents. Arch Intern Med 1960;106:816–23.
6. Moyer, J.H. Beazley, H.L. Effectiveness of Aramine in the Treatment of Shock. Am Heart J 1955;50:136–44.
7. Weil, M.H. Clinical Studies on a vasopressor agent: Metaraminol (Aramine). II Observations on its use in the management of Shock. Am J Med Sci 1955;230:357–69.
8. Stechel GH , Fishman SI , Schwartz G et al. The use of aramine in clinical shock. Circulation 1956;13: 834-836.