Best evidence topic reports Emerg Med J: first published as 10.1136/emermed-2017-206590.3 on 23 February 2017. Downloaded from

Three-part question Search outcomes In (adult patients presenting to the ED with MEDLINE search produced 35 papers. sepsis resulting in persistent hypotension EMBASE search produced 5 papers. not responding to fluid replacement) is CINAHL search produced 4 papers. a (peripheral metaraminol infusion as ProQuest search produced 55 papers. effective as central catecholamine infusion) PubMed search produced 150 papers. Cochrane database revealed one article of for (maintaining a blood pressure capable interest, but I was unable to obtain bar a of effective organ perfusion)? worldwide search and translation. NICE Evidence search identified no additional Clinical scenario relevant articles. A previously fit and well 36-year-old male College of Emergency Medicine website returns from a holiday to Greece 48 hours contained no relevant evidence or guide- ago and presents to the ED complaining lines. The Australian, American, Canadian of headache, malaise and feeling generally and New Zealand colleges of emergency unwell. While waiting to be seen, the medicine were searched but contained no patient’s headache rapidly worsens, he relevant evidence or guidelines. spikes a high temperature of 38.9°C, Citations from articles of interest were becomes increasingly agitated and starts also searched and revealed several new vomiting. He is taken to a resuscitation articles which appeared relevant to the cubicle and has a HR of 135 bpm and three-part question. However, these BP of 71/45 mm Hg. Examination of the were all predated publications from 1964. patient reveals several small non-blanching For most articles, I was unable to obtain petechiae. You manage the patient as an abstract, the abstract was in a ­foreign suspected meningitis and commence ­language and I was unable to obtain appropriate sepsis management. After any articles in full via internet or library administrating 3 L of intravenous fluid, searches. the patient remains with a systolic BP In total, eight articles were identified <80 mm Hg. The intensive care doctor that were relevant to the three-part ques- informs you that they are trying to make a tion (table 3). space available in the intensive treatment unit for this patient but are struggling to Comments step anyone down and the patient must Natalini et al specifically focused on remain in the resuscitation department. the comparison of noradrenaline and The resuscitation nurse asks you to metaraminol as a vasopressor for the prescribe more fluid. You wonder whether management of septic shock and revealed a peripheral metaraminol infusion would that there was no significant difference in be more effective at increasing arterial patient’s cardiac output, haemodynamic http://emj.bmj.com/ pressure and maintaining organ perfusion. variables or acid–base status. They also BET 3: Peripheral metaraminol found that there was no relationship in infusion in the emergency the doses provided to achieve patient department Search strategy optimisation. Hou et al demonstrated Ovid MEDLINE (1946 to present). that metaraminol infusion caused no Authors: Kenneth Anderson, Hridesh Chatha EMBASE (1974 to present) statistical difference to renal function over Affiliation: Stepping Hill Hospital, CINAHL (1981 to present) time regardless of the infusion strength. on September 24, 2021 by guest. Protected copyright. Stockport NHS Trust, Stockport, Manchester, UK ProQuest Database Makowski et al conducted a small study Pubmed Database which demonstrated that metaraminol can ABSTRACT Cochrane Database be given to good effect peripherally and A short cut review was carried out to NICE Evidence Database potentially be used for long periods of time. establish whether peripheral metaraminol The remaining studies demonstrated that College of Emergency Medicine infusions can be safely and effectively used metaraminol was an effective treatment A grey literature search was performed in emergency department patients. 239 for managing shock when compared with papers were found of which 8 presented via www.​google.​com, www.​opengrey.​eu other vasopressor therapies, both in terms the best evidence to answer the clinical and www.​controlled-​trials.​com​ of drug efficacy and patient mortality. All question. The author, date and country ([​metaraminol.​mp ​ or exp metaraminol] of the studies were small retrospective of publication, patient group studied, OR [​aramine.​mp​ or exp aramine] OR [​ or prospective cohort studies, with one study type, relevant outcomes, results and levicor.​mp] AND [​noradrenaline.​mp ​ or small crossover trial, at which the level study weaknesses of these best papers are exp norepinephrine] OR [​adrenaline.​mp​ of evidence was not very strong. One tabulated. The clinical bottom line is that or exp epinephrine] AND [​sepsis.​mp or of the studies was identified as a poster despite anecdotal evidence of common sepsis] OR [​hypotension.​mp or hypoten- presentation at an International anaesthetic usage there is limited high quality sion]). conference had only ever been published evidence to support the use of peripheral The references and citations of review in abstract form, making appraisal of the metaraminol as vasopressor support in the articles were also searched for articles rel- study findings impossible. All the papers emergency department. evant to the three-part question. had low numbers of patients, there were no 190 Emerg Med J March 2017 Vol 34 No 3 Best evidence topic reports Emerg Med J: first published as 10.1136/emermed-2017-206590.3 on 23 February 2017. Downloaded from Continued . No . Small patient numbers No washout period between No washout Small patient numbers ­ interpret. tudy weaknesses No power calculation. No control group. No control group. No power calculation. Retro- Unclear inclusion/exclusion criteria. spective reporting bias Old publication—less generalisable. Small Old publication—less generalisable. patient numbers (no power calculation). No description of randomi- No blinding. Urine flow data difficult sation technique. to S No randomisation of study drugs blinding of physicians or patients (although considered does state that this was ­ unethical for the patient group being studied). presentation at Poster Abstract only. Anaesthesia the Lisbon International ­ Conference 2012. No attempt to exclude different drugs. confounding factors No Old publication—less generalisable. Unclear description of inclusion criteria. for methodology as how drugs were given, Results in which combination. how long, section confusing as it lists results from other studies (both animal and various No attempt at randomisation, human trials). blinding or exclusion of confounding factors

L/

mls

­ normotensive satisfactory ­

mls (p=0.0001)

hours)

arterenol (1.7 vs asopressor therapy and were µg/kg/min) and metaraminol

µg/kg/min) doses (R²=0.087)

hours (range 1.5–144

hours before infusion 2570.64±1198.01

L/min/sq m) (p<0.01) or metaraminol (1.8 vs 2.8

hours after infusion 985±377.61

12 No statistical significant differences in the changes of these renal function parameters with time among the three groups 2. No significant difference demonstrated in global 2. No haemodynamic variables relationship between norepinephrine 3. No (0.30±0.28 2. 37.62 (2.5±1.7 0.01) min/sq m) (p, response to v Key results Key significant difference demonstrated in stroke 1. No volume index (mL/beats/m²) norepinephrine (40±15) metaraminol (40±15) (p=0.991) and HR (beats/min) ­ norepinephrine (96±15) metaraminol (95±21) (p=0.863) difference in acid–base status between 4. No ­ norepinephrine (− 4.2/−3.9) and M (−4.2/−3.8) (p=0.919) others 66% 34%, 1. Sepsis inserted in 36% of patients 3. CVCs 4. 12 ­ infusion of angiotensin vs lev 2.0 was significantly 10 of 12 patients urine flow 2. In reduced during angiotensin infusion compared with metaraminol or levarterenol. metaraminol exceeded previously reported with use of levarterenol All those who failed survived. Two patients. 3. Seven to respond metaraminol also failed levarterenol All those who failed to 11 survived. patients. 4. 31 Only respond to metaraminol were given levarterenol. one of those could reverse shock with eventual survival at death infusion) ­ Patient acid–base Patient Shock due to utcomes 1. Apache III 2. Urine out- III 2. Urine 1. Apache put (mL/hour) β 2- (mg/L) 4. U 3. U-ALB MG (mg/L) 5. BUN (µmol/L) (mmol/L) 6. CRE 2. Haemodynamic 2. Haemodynamic variables infusion time 2. Average 3. Drug doses 3. Drug O ­ 1. Detection of cardiac 1. Detection output >30% 4. status for starting 1. Reason metaraminol line insertion 3. Central (%) balance (before/ 4. Fluid after metaraminol (mean±SD) index1. Cardiac indexes were lower in all cases during 1. Cardiac flow 2. Urine due to MI1. Shock rate in those with Survival 13 survived. patients. 1. 20 due to sepsis2. Shock three had One survived, patients. 2. Nine 3. due to various 4. Shock causes haemorrhage

http://emj.bmj.com/ tudy type (level of Retrospective cohort. Observational study Observational (level 2b) S ­ ­ evidence) Prospective cohort study (level 2b) Prospective study (level 3) Prospective (level 2b) Prospective cohort study observation (level 3) observational observational crossover study arterenol ­ centred on September 24, 2021 by guest. Protected copyright. ­ intravenous ­ lev ­ (using (3) use of ­ metaraminol Norepinephrine ­ metaraminol mm Hg,

mm Hg.

­ respectively 0.6–1.0, >1.0 µg/kg), µg/kg), 0.6–1.0, >1.0 oup s diagnostic criteria) were divided into three groups atient gr P 10 patients admitted to a single Italian medical and surgical (1) intensive care unit who met following inclusion criteria: (2) adequate fluid resuscitation and diagnosis of septic shock, pulmonary artery occlusion pressure >14 norepinephrine to maintain MAP >65 and metaraminol 98 patients with septic shock Single centre study. ­ Hurford’ C) according to highest infusion rate of B, (A, used (0.1–0.5, 22 male) admitted to single- 47 patients (25 female, ­ surgical HDU who were started on peripheral infusion 12 patients with hypotension and clinical features of (noradrenaline, Levarterenol aetiology. shock from varying ­ infusion Six patients received angiotensin first followed by or other six patients received levarterenol The or metaraminol. metaraminol followed by angiotensin aetiology were given one 67 patients with shock from varying phenyle- metaraminol, or combination of mephentermine, Patients epinephrine and methoxamine. phrine, levarterenol, were selected at random and treated by resident staff faculty Metaraminol or angiotensin were administered by norepinephrine) ant papers Relev

et al , 1 2 3 4 5 uthor, year, year, uthor, Udhoji 1964, Makowski and Makowski Misztal, 2010, country of publication Natalini et al 2005, A ­ ­ Italy China UK USA USA Hou et al , 2007, Mills et al, 1960, Table 3 Table

Emerg Med J March 2017 Vol 34 No 3 191 Best evidence topic reports Emerg Med J: first published as 10.1136/emermed-2017-206590.3 on 23 February 2017. Downloaded from

randomised trials and the outcomes were not always clear. Several of the publications

. No . Small . 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 exclusion of blinding or randomisation techniques, and only Natalini et al set out a detailed inclusion criteria to attempt to reduce tudy weaknesses S Old publication—less generalisable blinding or attempt at randomisation, Small exclusion of confounding factors. patient numbers Old publication—less generalisable No attempt at randomisa- patient numbers. blinding or exclusion of confounding tion, factors ­ randomisation, Old publication—less generalisable. Old publication—less generalisable. No attempt at Small patient numbers. confounding factors confounding factors. Several of the selected papers were published over 50 years ago, mm 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 Duration of patient demographic.

hours Anecdotally, we know that peripheral

our of these subsequent- 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

mm Hg metaraminol against alternative circulatory

support strategies. min of infusion commencement.

potent as norepinephrine during intravenous ­ Key results Key as Hg (76%) established sustained systolic 2. 32 BP of ≥100 Methoxamine achieved a less satisfactory ly died. response than metaraminol when given both intramus- Phenylephrine cular and intravenous in five patients. effect when compared in two also produced a weaker patients. 1. 19/20 patients had a satisfactory response within 1. 19/20 8–10 ­ therapy lasted from 5 to 231.5 ­ ­ responding to metaraminolF 1. 36 (86%) established prompt systolic BP of ≥100 1. 36 (38%) survived to discharge 3. 16 gave a pressor response in five not 4. Norepinephrine 27 (64%) (36%) survived to hospital discharge. 1. 15 died during this admission Noradren- response to BP in six (14%) patients. 2. No aline substituted in 12 patients who had no prompt all of whom died despite this. response to metaraminol, administration Clinical bottom line

There is limited evidence to support ­ maintenance the use of peripheral metaraminol as ­vasopressor support in ED. Mortality utcomes O of 1. Efficiacy ­ doses2. Administration approximately 1/20 to 1/25 was 2. Metaraminol 2. Satisfactory to therapy 3. 1. Initial response to 1. Initial therapy 1. Mortality 4. Comparison with other 4. Comparison agents of metaraminol 2. Efficiacy infusion metaraminol infusion References 1 Natalini G, Schivalocchi V, Rosano A, et al. ­Norepinephrine and metaraminol in septic shock: a

comparison of the hemodynamic effects. Intensive Care http://emj.bmj.com/ 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 tudy type (level of S evidence) Prospective cohort study observational (level 3) Prospective ­ Retrospective ­ observational study observational (level 2b) (level 3) multicentred cohort observational study 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 ­ metaraminol the need for excessive fluid administration in the on September 24, 2021 by guest. Protected copyright. post-operative population. Intensive Care Med 2010;36:0342–4642. 4 Udhoji VN, Weil MH. 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 JH, Beazley HL. Effectiveness of aramine in the treatment of shock. Am Heart J 1955;50:136–44.

, 24 were treated with other vasopressor agents 24 were treated with other vasopressor , 7 Weil MH. Clinical studies on a vasopressor agent:

oup metaraminol (aramine). II. Observations on its use in the management of shock. Am J Med Sci 1955;230:357–69.

atient gr 8 Stechel GH, Fishman SI, Schwartz G, et al. The use of

P Ages ranged aetiology. 20 patients in clinical shock of various 14 males and from 23 to 93 years old (average age 63 years). Given metaraminol infusion alone or in combination 6 females. with noradrenaline All diagnosed with 42 patients included from four hospitals. Age range aetiology. unequivocal shock of various 18 were given 12–84 years (median age 61 years). infusion alone and effects were compared 250 patients admitted to a single centre in which the use of aetiology indicated for shock of varied was a vasopressor 42 cases reported in detail received metaraminol infusion. (remaining 208 cases were not included due to insufficient data concerning diagnosis or response to the drug) aramine in clinical shock. Circulation 1956;13:834–6. Emerg Med J 2017;34:190–192. doi:10.1136/emermed-2017-206590.3 Continued

7 6 8 uthor, year, year, uthor, country of publication Weil Weil , 1955, Stechel et al, 1956, A ­ ­ USA USA USA Moyer and Beazley, 1955, MAP, mean arterial pressure. MAP, Table 3 Table

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