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January 01, 2015

 

5 Questions to Ask During the Interview

 

You’ve updated your resume, you’ve received an interview appointment, you’ve researched the company on the internet, and now the interview is almost over and the Interviewer asks: “Do you have any questions for me”? If you say No to that question you are missing out on a great opportunity to learn more about the job and whether or not this is the opening for you!

Next time consider asking the following questions:

1. Is this a newly created position or are you replacing someone? You want to know why there is a vacancy. It’s a good sign if the person was promoted and a not so good sign if they “didn’t work out.”

2. What strengths do you believe a successful person in this position should have? With this information you will be able to include some of those strengths at the end of the interview during your final wrap-up.

3. What are some of the challenges in this position? Most jobs have some things that call for certain tolerance levels, i.e., workload, schedule constraints, etc. Be prepared — the Interviewer may turn this question back to you and ask you directly how you would handle those challenges.

4. Can you describe a typical day? This question can be interchanged with the previous question as usually the answer about challenges may include a description of a typical day and vice versa.

5. When do you plan to make a decision about this position? By understanding the recruitment timeline you’ll have a better idea of when you can expect to hear from them. This information is usually offered but if they don’t mention it you can ask.

There is nothing worse than asking a question that has already been answered. Your questions could work against you if you’re not paying attention.

Remember not to go overboard with the questions, gauge your interviewers and the time you have available. They have probably allowed only so much time for each candidate. If they don’t ask you about asking questions, ask them if you can ask a few questions. Move through your questions succinctly.

Asking questions allows you to more fully participate in the interview process. The questions listed here are examples to get you thinking about questions you may want to formulate. Be brief, relative, and relax!

Vitaly Golyakov



December 17, 2014

ERRATUM
Erratum to: Do heart and respiratory rate
variability improve prediction of extubation
outcomes in critically ill patients?
Andrew JE Seely1,2,11*, Andrea Bravi2, Christophe Herry1, Geoffrey Green1, André Longtin2, Tim Ramsay1,
Dean Fergusson1, Lauralyn McIntyre1, Dalibor Kubelik1, Donna E Maziak1, Niall Ferguson3, Samuel M Brown4,
Sangeeta Mehta5, Claudio Martin6, Gordon Rubenfeld7, Frank J Jacono8, Gari Clifford9, Anna Fazekas1,
John Marshall10 and The Canadian Critical Care Trials Group (CCCTG)
See related research by Seely et al., http://ccforum.com/content/18/2/R65
Erratum
While compiling this article [1] one of the authors was
inadvertently omitted from the author list. This author,
The Canadian Critical Care Trials Group (CCCTG), has
been included in the corrected author list above.
Competing interests
Andrew Seely is Founder and Chief Science Officer of Therapeutic
Monitoring Systems (TMS); TMS aims to commercialize patent-protected
applications of multiorgan variability monitoring to provide variability-directed
clinical decision support at the bedside to improve care for patients at risk
for or with existing critical illness. Andrew Seely holds a patent jointly with
co-authors Andrea Bravi and André Longtin on composite measures of
variability. Geoffrey Green is Product Manager for TMS. John Marshall and
Gari Clifford are on the Scientific Advisor Board of TMS. Other authors have
no relevant conflict of interest to disclose.
Acknowledgements
Members of the Canadian Critical Care Trials Group (CCCTG):
Dr Jon Hooper, Tracy McArdle, Shawna Reddie, Dr Peter Wilkes, Denyse
Winch, Dr Claudio Martin, Eileen Campbell, Dr Sangeeta Mehta, Maedean
Brown, Dr Peter Dodek, Betty Jean Ashley, Dr John Marshall and Orla Smith.
Author details
1Ottawa Hospital Research Institute, 725 Parkdale Avenue, Ottawa, ON K1Y 4E9,
Canada. 2University of Ottawa, 75 Laurier Avenue East, Ottawa, ON K1N 6N5,
Canada. 3University Hospital Network, University of Toronto, 190 Elizabeth
Street, Toronto, ON M5G 2C4, Canada. 4Intermountain Medical Center (IMC),
Shock Trauma ICU, 5121 Cottonwood Street, Murray, UT 84157, USA. 5Mt Sinai,
University of Toronto, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
6London Health Sciences Center, 339 Windermere Road, London, ON N6G 2V4,
Canada. 7Sunnybrook Hospital, University of Toronto, 2075 Bayview Avenue,
Toronto, ON M4N 3M5, Canada. 8University Hospital Case Medical Center, Case
Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106, USA.
9University of Oxford, Kellogg College, Banbury Road, Oxford OX2 6PN, United
Kingdom. 10St. Michaels Hospital, University of Toronto, 30 Bond Street, Toronto,
ON M5B 1W8, Canada. 11Divisions of Thoracic Surgery & Critical Care Medicine,
501 Smyth Road, Ottawa, ON K1H 8L6, Canada.
Reference
1. Seely AJE, Bravi A, Herry C, Green G, Longtin A, Ramsay T, Fergusson D,
McIntyre L, Kubelik D, Maziak DE, Ferguson N, Brown SM, Mehta S, Martin C,
Rubenfeld G, Jacono FJ, Clifford G, Fazekas A, Marshall J: Do heart and
respiratory rate variability improve prediction of extubation outcomes in
critically ill patients? Crit Care 2014, 18:R65.
doi:10.1186/s13054-014-0620-z
Cite this article as: Seely et al.: Erratum to: Do heart and respiratory rate
variability improve prediction of extubation outcomes in critically ill
patients? Critical Care 2014 18:620.
* Correspondence: aseely@ohri.ca
1Ottawa Hospital Research Institute, 725 Parkdale Avenue, Ottawa, ON K1Y
4E9, Canada
2University of Ottawa, 75 Laurier Avenue East, Ottawa, ON K1N 6N5, Canada
© 2014 Seely et al.; licensee BioMed Central Ltd. The licensee has exclusive rights to distribute this article, in any medium, for
12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://
creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Seely et al. Critical Care 2014, 18:620
http://ccforum.com/content/18/6/620

December 16, 2014

Protti et al. Critical Care 2010, 14:R22
http://ccforum.com/content/14/1/R22
RESEARCH Open Access
© 2010 Protti et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
Research Oxygen consumption is depressed in patients with
lactic acidosis due to biguanide intoxication
Alessandro Protti*1, Riccarda Russo1, Paola Tagliabue2, Sarah Vecchio3, Mervyn Singer4, Alain Rudiger5, Giuseppe Foti2,
Anna Rossi6, Giovanni Mistraletti7 and Luciano Gattinoni1
Abstract
Introduction: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a
consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen
consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide
intoxication.
Methods: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 ± 0.20;
lactate 18 ± 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients,
VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and
cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available.
Results: On day 1, VO2 was markedly depressed (67 ± 28 ml/min/m2) despite a normal CI (3.4 ± 1.2 L/min/m2). C(a-v)O2
was abnormally low in both patients either with (2.0 ± 1.0 ml O2/100 ml) or without (2.5 ± 1.1 ml O2/100 ml) CI (and
VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel
increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n
= 32).
Conclusions: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line
with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia.
Introduction
Metformin and phenformin are oral anti-diabetic drugs of
the biguanide class. Metformin is the first-line drug of
choice for the treatment of adults with type 2 diabetes [1]. It
is the 10th most frequently prescribed generic drug in the
USA (>40 million prescriptions in 2008) and is currently
used by almost one-third of diabetic patients in Italy [2,3].
Phenformin is no longer on sale in many countries, but is
still available in Italy.
Lactic acidosis can develop in patients taking metformin
or phenformin, especially when renal failure leads to drug
accumulation [4-6]. According to the American Association
of Poison Control Centers, metformin was implicated in 19
fatalities in the USA in 2007 [7]. Thirty cases of biguanide
intoxication have been reported over the past two years to
the Poison Control Centre of Pavia, Italy, resulting in 10
deaths (Dr Sarah Vecchio, unpublished data). The progressive
increase in metformin use (20% rise in prescriptions
between 2006 and 2008 in the USA) may result in a parallel
increase in the incidence of associated lactic acidosis [2,8].
The pathogenesis of biguanide-associated lactic acidosis
remains unclear, especially when it develops in the absence
of other major risk factors such as hypoxia, tissue hypoperfusion,
or liver failure (biguanide-induced lactic acidosis).
Hyperlactatemia is classically attributed to an impaired lactate
clearance, secondary to an exaggerated inhibition of
hepatic gluconeogenesis [9] but may also depend on an
increased lactate production by the liver [10] or the intestine
[11].
Biguanide drugs mainly exert their therapeutic effect by
impairing hepatocyte mitochondrial respiration [12,13].
Recent observations have suggested that metformin, similarly
to phenformin, might also inhibit mitochondrial respi-
* Correspondence: alessandro.protti@policlinico.mi.it
1 Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
di Milano, Università degli Studi di Milano, Via F. Sforza 35, 20122 Milan, ItalyProtti et al. Critical Care 2010, 14:R22
http://ccforum.com/content/14/1/R22
Page 2 of 9
ration in tissues other than the liver [14-16]. Mitochondria
produce energy while consuming oxygen (O2) and releasing
carbon dioxide (CO2) and heat. When O2 provision or utilization
are compromised, cellular energy production can
partly rely on the extra-mitochondrial anaerobic lactate
generation, that is associated with metabolic acidosis. As
mitochondrial respiration normally accounts for more than
90% of whole body O2 utilization and CO2 release, any
defect in mitochondrial metabolism will decrease systemic
O2 consumption and CO2 production.
We hypothesize that inhibition of mitochondrial respiration
is responsible for the development of lactic acidosis
during metformin or phenformin intoxication. If our
hypothesis is correct, respiration should be abnormally low
regardless of any change in systemic O2 delivery. The aim
of this study is to investigate global O2 consumption (and
CO2 production) in patients with lactic acidosis due to biguanide
intoxication.
Materials and methods
We reviewed the data sheets of patients admitted to 12
intensive care units and 1 nephrology unit of 11 hospitals
from January 2005 to June 2009, with a discharge diagnosis
of lactic acidosis due to biguanide intoxication. Patients
with a concomitant primary diagnosis of septic or cardiogenic
shock or liver failure were excluded. Lactic acidosis
was defined as pH less than 7.30 and plasma lactate more
than 5 mM. Only patients with central or mixed venous O2
saturation monitoring were included.
We calculated the arterio-venous difference in O2 content
[C(a-v)O2] as:
where CaO2 and CvO2 are arterial and venous blood O2
content, respectively, Hb is blood hemoglobin concentration,
SaO2 is arterial O2 saturation, SvO2 is O2 saturation of
blood taken from the superior vena cava or the pulmonary
artery (collectively indicated as central venous blood) and
PaO2 and PvO2 are the arterial and central venous O2 tensions.
Oxygen extraction index (OEI) was defined as:
and expressed as a percentage. The veno-arterial difference
in CO2 content [C(v-a)CO2] was calculated according
to Douglas and colleagues [17]. In patients with cardiac
index (CI) monitoring, we calculated whole body O2 delivery
(DO2) as CI × CaO2 and O2 consumption (VO2) as CI ×
C(a-v)O2, with CI computed as cardiac output divided by
estimated body surface area. Carbon dioxide production
(VCO2) was calculated as CI × C(v-a)CO2.
The severity of illness was initially expressed by the Simplified
Acute Physiology Score (SAPS) II [18] and then
monitored using the Sequential Organ Failure Assessment
(SOFA) score [19]. The cardiovascular SOFA score was
used to describe catecholamine requirements. Sedation was
evaluated using the Richmond Agitation Sedation Scale
(RASS) [20]. Heart rate, body temperature and need for
mechanical ventilation were also recorded. Analysis was
restricted to the first four days following admission, or until
discharge or death if any of these occurred earlier.
The local Ethics Committee of the coordinating Centre
(Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli
e Regina Elena di Milano, Italy) was informed of
the ongoing retrospective analysis and did not require any
specific informed consent.
Statistical analysis
Results are presented as mean ± standard deviation or
median and interquartile range, based on data distribution
(Kolmogorov-Smirnov test). The relation between serum
metformin levels and other variables was assessed using
linear regression analysis and expressed as R2. Severity of
illness at admission of patients with or without CI monitoring
was compared using the Student's t-test. The remainder
of the analyses were performed on data averaged on a daily
basis. Changes occurring over time were investigated using
parametric or non-parametric one-way repeated-measures
analysis of variance. Post-hoc comparisons were performed
using Bonferroni or Dunn's test, considering day 1 as baseline.
The relation between the arterio-venous difference in
O2 content and the veno-arterial difference in CO2 content
was calculated using linear regression. The relation
between systemic O2 consumption and other variables was
investigated using linear (arterial pH) or non-linear (body
temperature and plasma lactate) regression. The chisquared
test was used to assess whether the proportion of
patients requiring mechanical ventilation changed over
time. Analysis was performed using Sigma Stat version
3.1.1 (Jandel Scientific Software; San Jose, CA, USA). A
two-sided P value less than 0.05 was considered as statistically
significant.
Results
We identified 24 diabetic patients admitted to the intensive
care (n = 22) or nephrology (n = 2) units with lactic acidosis
attributed to either metformin (n = 23) or phenformin (n =
1) intoxication (Table 1). Seventeen (71%) were females
and the mean age of all patients was 66 ± 9 years.
Lactic acidosis on hospital admission was always severe,
with an arterial pH of 6.93 ± 0.20 and lactate of 18 ± 6 mM.
Blood glucose level was 118 ± 78 mg/dl, with severe hypoglycemia
(<40 mg/dl) being present in 3 patients. Liver
CaO CvO Hb SaO PaO
Hb SvO Pv
22 2 2
2
1 39 0 003
1 39 0 003
− = ×× + ×
− ×× + ×
(. . )
(. . O2),
( )/ CaO CvO CaO 22 2 −Protti et al. Critical Care 2010, 14:R22
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Page 3 of 9
Table 1: Main characteristics of the study population
Id Intoxicant Serum
drug level
(μg/ml)
Creatinine
(mg/dl)
pH Lactate
(mM)
Monitoring SAPS II ICU
outcome
1 Metformin 70 6.4 7.21 22 CI; 58 S
2 Metformin 63 12.4 6.95 33 CI; 53 S
3 Metformin NA 10.8 6.76 21 CI; 61 S
4 Metformin NA 15.2 7.06 18 CI; 51 S
5 Metformin NA 9.0 6.63 21 CI; 55 S
6 Metformin NA 10.3 6.82 21 CI; ScvO2 87 S
7 Metformin NA 10.8 6.70 24 CI; ScvO2 74 S
8 Metformin 61 1.9 7.27 10 CI; 83 NS
9 Metformin NA 13.2 6.79 21 CI; ScvO2 63 S
10 Metformin NA 4.7 7.13 19 CI; ScvO2 66 S
11 Metformin 53 4.5 <6.80 16 CI; 87 NS
12 Metformin 65 8.4 6.76 22 ScvO2 43 S
13 Phenformin 480§ 9.5 6.91 13 ScvO2 59 S
14 Metformin 100 5.8 7.26 10 ScvO2 58 S
15 Metformin 63 4.2 6.89 18 ScvO2 53 NS
16 Metformin NA 13.0 6.93 17 ScvO2 67 S
17 Metformin 19† 9.9 6.62 19 ScvO2 62 S
18 Metformin NA 6.1 <6.80 24 ScvO2 70 NS
19 Metformin 100 7.6 6.87 16 ScvO2 45 S
20 Metformin 25† 9.3 6.81 15 ScvO2 44 S
21* Metformin 70 4.8 7.22 11 ScvO2 66 S
22* Metformin 44 10.0 6.93 14 ScvO2 55 S
23 Metformin NA 13.8 7.21 6 ScvO2 39 S
24 Metformin NA 7.1 6.93 17 ScvO2 65 NS
The first available serum drug concentration (§ phenformin in ng/ml;† blood sample obtained with ongoing renal replacement therapy),
creatinine level, arterial blood pH and plasma lactate level, available data (CI, cardiac index; ScvO2, central venous oxymetry; , mixed
venous oxymetry), severity of the disease (expressed as Simplified Acute Physiology Score (SAPS) II score) and outcome (S = survivor; NS =
non survivor) are reported. Target values in patients on metformin or phenformin are less than 4 μg/ml and less than 140 ng/ml, respectively.
ICU, intensive care unit; NA, not available; * patients admitted to the Nephrology Unit.
SvO 2
SvO 2
SvO 2
SvO 2
SvO 2
SvO 2
SvO 2
SvO 2
function tests were usually normal, with alanine aminotransferase
66 ± 78 IU/L, total bilirubin 0.4 ± 0.2 mg/dl,
albumin 33 ± 6 g/L, and prothrombin time (expressed as
international normalized ratio) 1.2 ± 0.3 (excluding two
patients on warfarin). Left ventricular ejection fraction,
investigated in seven patients by echocardiography, was
always normal (≥ 50%).
Intoxication was always accidental and associated with
renal failure (creatinine 8.7 ± 3.5 mg/dl, urea 171 ± 70 mg/
dl and oligo-anuria) and continued drug intake. Factors
potentially implicated in the development of renal failureProtti et al. Critical Care 2010, 14:R22
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Page 4 of 9
were dehydration (a history of several days' vomiting and/
or diarrhea was reported in 75% of the cases), urinary tract
infection (29%) and chronic renal dysfunction (21%).
Whenever measured, serum drug concentration on day 1
was always well above safe limits (metformin 61 ± 25 vs.
<4 μg/ml, n = 12; phenformin 480 vs. <140 ng/ml, n = 1).
Metformin levels, measured at different time points in 10
patients, were positively correlated with those of creatinine
(R2 = 0.34; P < 0.001, n = 29) and lactate (R2 = 0.49; P <
0.001, n = 29) and inversely correlated with arterial pH (R2
= 0.68; P < 0.001, n = 29).
Treatment included the use of mechanical ventilation (n =
16), catecholamines (n = 21) and renal replacement therapy
(n = 21). The first day SAPS II score was 61 ± 13, corresponding
to an expected mortality of approximately 70%.
Observed mortality was 21%.
Central venous O2 saturation was monitored through a
central venous (n = 17) or pulmonary artery (n = 7) catheter.
Blood gases were always measured at 37°C. In 11 patients,
CI was also measured, using the PiCCO system (n = 2),
transesophageal Doppler ultrasonography (n = 2) or pulmonary
artery catheter thermodilution (n = 7). Patients with CI
monitoring had a higher SAPS II (67 ± 14 vs. 56 ± 10; P <
0.05) and SOFA (12 ± 3 vs. 9 ± 2; P < 0.05) scores on
admission.
Main results are reported in Table 2 and Figures 1 and 2.
Systemic O2 consumption, monitored in 11 patients, was
abnormally low on day 1 and normalized within the next 48
to 72 hours (P < 0.001), paralleled by resolution of lactic
acidosis (P < 0.001). As systemic O2 delivery did not significantly
change compared with day 1, variations in whole
body O2 consumption were reflected in equal changes in
Table 2: Temporal changes observed in 11 biguanide-intoxicated patients with cardiac index and central venous oxygen
saturation monitoring
n Day 1 Day 2 Day 3 Day 4 P
pH 11 7.03
(6.92-7.15)
7.35
(7.25-7.40)
7.44
(7.35-7.46)*
7.46
(7.44-7.47)*
<0.001
Lactate (mM) 11 17 (14-20) 5 (2-15) 2 (2-3)* 1 (1-3)* <0.001
VO2 (ml/min/m2) 9 67 ± 28 99 ± 30* 116 ± 41* 129 ± 42* <0.001
DO2 (ml/min/m2) 9 443 ± 167 572 ± 152 491 ± 95 430 ± 116 <0.01
CI (L/min/m2) 9 3.4 ± 1.2 4.4 ± 1.3 3.9 ± 0.8 3.4 ± 1.2 0.08
C(a-v)O2
(ml O2/100 ml)
10 2.0 ± 1.0 2.4 ± 0.8 2.9 ± 0.8* 3.8 ± 1.4* <0.001
SvO2 (%) 10 83 ± 8 80 ± 6 75 ± 5* 70 ± 8* <0.001
OEI (%) 10 13 (11-19) 16 (13-21) 23 (21-25)* 31 (23-34)* <0.001
C(v-a)CO2
(ml CO2/100 ml)
7 2.2 ± 0.8 2.2 ± 0.8 3.9 ± 1.9 4.7 ± 1.2* <0.05
RASS 11 -4 (-5--2) -4 (-4--1) -2 (-4-0) -1 (-3-0) 0.06
On MV (%) 11 91 100 67 67 0.12
HR 11 103 ± 20 104 ± 8 99 ± 16 97 ± 21 0.74
SOFA 11 12 ± 3 10 ± 1* 9 ± 2* 10 ± 2* <0.001
Catecholamine
use (SOFA sub
score)
11 4 (4-4) 4 (4-4) 4 (4-4) 3 (2-3)* <0.001
BT (°C) 10 34.5 ± 2.2 36.6 ± 0.6* 36.8 ± 0.4* 36.7 ± 0.5* <0.001
Results of repeated-measures analysis of variance and chi-squared test are reported in the right column. Data significantly different from day
1 on post-hoc comparison are indicated as *. n is the number of patients with each specific variable monitored on day 1.BT, body temperature;
C(a-v)O2, arterio-venous difference in oxygen content; C(v-a)CO2, veno-arterial difference in carbon dioxide content; CI, cardiac index; DO2,
systemic oxygen delivery; HR, heart rate; MV, mechanical ventilation; OEI, oxygen extraction index; RASS, Richmond Agitation Sedation Score;
SOFA, Sequential Organ Failure Assessment; SvO2, central venous oxygen saturation; VO2, systemic oxygen consumption.Protti et al. Critical Care 2010, 14:R22
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arterio-venous difference in O2 content and O2 extraction
index and opposite changes in central venous O2 saturation
(P < 0.001 for all). The difference in veno-arterial CO2 content
was abnormally low on day 1 and progressively
returned to normal (P < 0.05). Whole body CO2 production
showed a similar, although not significant, trend, rising
from 93 ± 24 (on day 1) to 115 ± 13 ml/min/m2 (on day 4; n
= 4). The arterio-venous difference in O2 content was positively
associated with the veno-arterial difference in CO2
content (R2 = 0.42; P = 0.001, n = 22). Systemic O2 consumption
was positively associated with arterial pH (R2 =
0.37; P < 0.001, n = 32) and body temperature (R2 = 0.38; P
< 0.001, n = 30) and inversely correlated with plasma lactate
(R2 = 0.43; P < 0.001, n = 32).
Major findings remained valid when the analysis was
restricted to the 7 patients monitored with a pulmonary
artery catheter. From day 1 to 4, lactate levels decreased
from 16 (13 to 19) to 1 (1 to 2) mM (P < 0.01). Global O2
consumption increased (81 ± 21 vs. 129 ± 47 ml/min/m2; P
= 0.01) despite no change in systemic O2 delivery (482 ±
180 vs. 441 ± 139 ml/min/m2; P = 0.10). The arteriovenous
difference in O2 content (2.3 ± 1.2 vs. 3.9 ± 1.1 ml
O2/100 ml; P = 0.001) and the O2 extraction index (17 ± 7
vs. 30 ± 6%; P < 0.001) augmented and the mixed venous
O2 saturation accordingly decreased (81 ± 9 vs. 69 ± 6%; P
= 0.001). The difference in veno-arterial CO2 content
increased from 2.4 ± 0.7 to 4.6 ± 1.5 ml CO2/100 ml (P <
0.05). Systemic O2 consumption inversely correlated with
plasma lactate (R2 = 0.30; P = 0.01, n = 21).
In patients without CI monitoring, initial values and later
changes in the other variables of interest closely resembled
those observed in monitored patients (Table 3).
Twelve patients had one or more simultaneous determinations
of serum metformin levels and arterio-venous differFigure
1 Relation between cardiac index and arterio-venous difference in oxygen content in biguanide-intoxicated patients. Cardiac index
(CI) and arterio-venous difference in oxygen content [C(a-v)O2] recorded during the first 4 days of admission from 11 biguanide-intoxicated patients.
Each circle refers to individual data averaged on a daily basis. The arterio-venous difference in oxygen content was computed from either mixed (black
circles) or central (white circles) venous oxygen saturation. Dotted lines refer to the lower and upper limits of normal systemic oxygen consumption
(110 to 160 ml/min/m2). Circles that are located under the lower dotted line indicate an arterio-venous difference in oxygen content (oxygen extraction)
lower than expected if systemic oxygen consumption is normal. C(a-v)O2 (ml O2/100 ml)
CI (L/min/m2 CI (L/min/m ) 2)
C(a-v)O2 (ml O2/100 ml) C(a-v)O2 (ml O2/100 ml)
CI (L/min/m2) CI (L/min/m2) C(a-v)O2 (ml O2/100 ml)
Day 1 Day 2
Day 3 Day 4Protti et al. Critical Care 2010, 14:R22
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Page 6 of 9
ence in O2 content; an inverse correlation was noted
between these variables (R2 = 0.20; P < 0.05, n = 22).
Discussion
The present study demonstrates that whole body O2 consumption
(and CO2 production) are abnormally low during
biguanide-induced lactic acidosis and return to normal on
recovery from drug intoxication.
Metformin is a safe drug when correctly prescribed [21].
Lactic acidosis can develop in cases of drug accumulation
but is usually attributed to other concomitant precipitating
factors. However, some reports suggest that metformin
accumulation may cause lactic acidosis even in the absence
of other obvious confounding variables [22]. According to
discharge diagnosis, patients included in this present study
suffered from lactic acidosis (better defined as hyperlactatemia
with metabolic acidosis) mainly attributed to (documented
or suspected) metformin or phenformin
intoxication. None of the patients had any sign of acute
liver or cardiac failure. Acute renal failure was invariably
present at hospital admission, but could have hardly represented
the sole cause of such a dramatic rise in blood lactate
levels. Septic shock was never reported as the primary diagFigure
2 Relation between systemic oxygen consumption and
lactatemia in biguanide-intoxicated patients. Systemic oxygen
consumption (VO2), computed from either mixed (black circles) or central
(white circles) venous oxygen saturation, inversely correlated with
plasma lactate (R2 = 0.43; P < 0.001; n = 32).
Table 3: Temporal changes observed in 13 biguanide-intoxicated patients with central venous oxygen saturation (but not
cardiac index) monitoring
n Day 1 Day 2 Day 3 Day 4 P
pH 13 7.14 ± 0.17 7.36 ± 0.10* 7.45 ± 0.09* 7.43 ± 0.06* <0.001
Lactate (mM) 13 12 ± 6 5 ± 8* 2 ± 1* 2 ± 1* <0.001
C(a-v)O2
(ml O2/100 ml)
12 2.5 ± 1.1 3.1 ± 1.0 3.4 ± 0.8 4.2 ± 1.2* <0.05
SvO2 (%) 12 79 ± 10 75 ± 10 73 ± 6* 66 ± 7* 0.01
OEI (%) 12 20 ± 10 24 ± 10 25 ± 7 33 ± 7* 0.01
C(v-a)CO2
(ml CO2/100 ml)
8 2.4 ± 1.6 2.8 ± 1.2 3.6 ± 0.9 5.5 ± 1.9 0.16
RASS 13 -1 (-4-0) 0 (-3-0) 0 (-1-0) -1 (-3-0) 0.05
On MV (%) 13 31 42 27 38 0.89
HR 12 87 ± 17 88 ± 15 91 ± 14 88 ± 8 0.10
SOFA 13 9 ± 2 8 ± 3 6 ± 3* 7 ± 3* <0.001
Catecholamine
use (SOFA sub
score)
13 3 ± 2 3 ± 2 2 ± 2* 2 ± 2* <0.01
BT (°C) 10 35.8
(35.0-36.3)
36.8
(36.4-37.3)
37.0
(36.7-37.5)*
36.9
(36.6-37.4)
<0.05
Results of repeated-measures analysis of variance and chi-squared test are reported in the right column. Data significantly different from day
1 on post-hoc comparison are indicated as *. n is the number of patients with each specific variable monitored on day 1.
BT, body temperature; C(a-v)O2, arterio-venous difference in oxygen content; C(v-a)CO2, veno-arterial difference in carbon dioxide content;
HR, heart rate; MV, mechanical ventilation; OEI, oxygen extraction index; RASS, Richmond Agitation Sedation Score; SOFA, Sequential Organ
Failure Assessment; SvO2, central venous oxygen saturation.Protti et al. Critical Care 2010, 14:R22
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Page 7 of 9
nosis. Sepsis may still have acted as a precipitating factor
(gastroenteritis, urinary tract infection) but could not
explain our present initial findings. Indeed, systemic O2
consumption is usually normal or even increased in critically
ill septic patients, at least in the early phase [23,24].
The most common cause of lactic acidosis in critically ill
patients is probably cellular hypoxia. When O2 delivery
acutely decreases due to low cardiac output, anemia or
hypoxemia, tissue O2 extraction rises in an attempt to preserve
aerobic mitochondrial respiration. The arterio-venous
difference in O2 content, that is the ratio between whole
body O2 consumption and cardiac output, increases and
central venous O2 saturation decreases. Oxygen consumption
only starts to diminish when O2 delivery falls below a
critical value; the blood lactate concentration then abruptly
increases, indicating the development of anaerobic metabolism
[25]. The veno-arterial difference in CO2 content, that
depends on the ratio between CO2 production and cardiac
output, may rise as well, mainly as a consequence of a
reduced cardiac output.
Lactic acidosis can also develop under aerobic conditions,
when O2 utilization is prevented by mitochondrial
dysfunction, glycolysis is overly stimulated or lactate clearance
is impaired [26-28]. Growing evidence, mainly
derived from cell and animal studies, suggest that metformin
and phenformin can actually interfere with mitochondrial
respiration in a dose-dependent manner [10,12-
14]. By interfering with mitochondrial respiration in the
liver, they decrease gluconeogenesis (and lactate clearance)
and may potentially increase glucose consumption (and lactate
production) [10,12,13]. Although the effect on organs
and tissues other than the liver is less clear, metformin can
still diminish mitochondrial respiration and increase glycolysis
(and lactate release) in the skeletal muscle [14].
Whether the drug can decrease global O2 consumption in
either animals or humans remains poorly investigated and
unclear [29-31]. Based on these observations, we hypothesize
that during metformin or phenformin accumulation, the
inhibition of mitochondrial respiration is so strong that the
production of lactate (by the liver and, probably, other tissues)
increases above the residual capacity of the body to
clear it, leading to the development of lactic acidosis.
Our results support this hypothesis. In fact, systemic O2
consumption, measured in 11 patients, was markedly
depressed in the early phase, when lactic acidosis was more
dramatic, despite a normal, or even increased, O2 delivery.
This finding may be cautiously extended to 13 additional
patients in whom systemic O2 consumption could not be
computed, from initial recording of very low values of arterio-venous
difference in O2 content, diminished peripheral
O2 extraction and increased central venous O2 saturation.
Similar changes occur after exposure to cyanide, a wellknown
inhibitor of mitochondrial respiration [32]. Even if
acidosis was more likely the result of a diminished mitochondrial
respiration, it might have also contributed to further
decrease the systemic energy expenditure and O2
consumption [33]. However, the basal systemic O2 consumption
of 15 critically ill, mechanically ventilated
patients enrolled in a previous trial led by our group, with
an arterial pH below 7.20, was 123 ± 65 ml/min/m2 [34].
Alterations in O2 consumption were apparently paralleled
by changes in CO2 production. Direct measurement of systemic
CO2 production using the reverse Fick equation
requires calculation of the whole blood veno-arterial difference
in CO2 content. This primarily consists of physically
dissolved CO2, bicarbonate ions and carbamino compounds.
As whole blood CO2 content is not routinely measured,
we computed it using an algorithm that includes the
CO2 tension, pH, hemoglobin concentration and O2 saturation
[17]. Similar to arterio-venous difference in O2 content,
the initially low difference between venous and arterial CO2
content is suggestive of diminished CO2 production.
Previous studies have demonstrated that severity of illness,
use of sedatives and catecholamines, heart rate, body
temperature and mechanical ventilation can all affect resting
energy expenditure [35,36]. Overall, systemic O2 consumption,
arterio-venous difference in O2 content and venoarterial
difference in CO2 content reached their nadir when
severity of illness and use of catecholamines were at their
highest values. Patient awakening occurred slowly, well
after the normalization of O2 consumption and related variables.
Heart rate and the need for mechanical ventilation
did not significantly change over time. A body temperature
on hospital admission averaging 34 to 35°C cannot, in isolation,
explain the observed 40 to 60% reduction in systemic
O2 consumption, because O2 consumption should
diminish by approximately 5 to 6% for every 1°C fall in
temperature [37,38]. Moreover, the systemic O2 consumption
of 25 critically ill patients, with a body temperature
between 34 to 35°C, was 136 ± 40 ml/min/m2 [34]. None of
the patients included in the present study had any obvious
reason to be hypothermic on hospital admission: they usually
arrived from home, were awake and with pale, cold
extremities. Hypothermia was more likely the consequence
of the biguanide-induced decrease in metabolic rate. Even
if abnormally low body temperature may impact upon the
interpretation of the blood gas analyses performed at 37°C,
temperature correction is unnecessary to compute the arterio-venous
differences in O2 and CO2 content [39].
Some of the limitations of this present study deserve a
comment. First, we did not include any control group,
because of the peculiar characteristics of the study population.
However, every single patient with biguanide intoxica-Protti et al. Critical Care 2010, 14:R22
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Page 8 of 9
tion acted as an internal control, with individual recordings
of global O2 consumption (and CO2 production) being significantly
lower on day 1, relative to the following days.
Second, we used the central venous O2 saturation to compute
global O2 consumption of patients equipped with a cardiac
output monitoring but not a pulmonary artery catheter.
As catecholamine use did not change over time in these
subjects, changes in central venous O2 saturation (and
derived variables) likely reflected those in mixed venous O2
saturation. Moreover, when the analysis was restricted to
the 7 patients equipped with a pulmonary artery catheter,
the major findings of the study remained valid. Third, the
respiratory quotient - the ratio between the difference in
CO2 and O2 content of simultaneously drawn arterial and
venous blood samples - sometimes exceeded one, an unexpected
finding, at least at steady state. Possible explanations
include the fact that, in our study population, blood gas
analysis were not performed at steady state and blood CO2
content was estimated rather than directly measured. We
cannot, however, definitely exclude the occurrence of any
error in blood sampling, gas analysis or data reporting.
Conclusions
Metformin and phenformin intoxication is characterized by
severe lactic acidosis and abnormally low systemic oxygen
consumption despite normal or even increased systemic
oxygen delivery. These findings are consistent with the
hypothesis that biguanide drugs cause lactic acidosis by
inhibiting mitochondrial respiration, without any clear evidence
of cellular hypoxia. Cause and effect still needs to be
conclusively demonstrated.
Key messages
• The progressive increase in metformin use may result
in a parallel increase in the incidence of associated lactic
acidosis.
• The pathogenesis of biguanide-associated lactic acidosis
remains unclear, especially when it develops in the
absence of other major risk factors.
• Biguanide intoxication is characterized by severe lactic
acidosis and abnormally low systemic O2 consumption,
despite normal or even increased global oxygen
delivery.
• Resolution of drug intoxication is paralleled by correction
of lactic acidosis and normalization of systemic
O2 consumption.
• These findings are in line with the hypothesis that lactic
acidosis develops during metformin or phenformin
intoxication because of inhibition of mitochondrial respiration.
Abbreviations
C(a-v)O2: arterio-venous difference in oxygen content; C(v-a)CO2: veno-arterial
difference in carbon dioxide content; CaO2: arterial blood oxygen content;
CvO2: venous blood oxygen content; CI: cardiac index; CO2: carbon dioxide;
DO2: systemic oxygen delivery; O2: oxygen; OEI: oxygen extraction index; PaO2:
arterial venous oxygen tensions; PvO2: central venous oxygen tensions; RASS:
Richmond Agitation Sedation Score; SAPS II: Simplified Acute Physiology Score
II; SaO2: arterial oxygen saturation; SOFA: Sequential Organ Failure Assessment;
SvO2: central venous oxygen saturation; VCO2: systemic carbon dioxide production;
VO2: systemic oxygen consumption.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AP conceived the study, participated in its design and coordination, performed
the statistical analysis and drafted the manuscript. RR, PT, and SV participated
in study design and data collection. MS, AR, and GF participated in data collection,
interpretation of data and helped to draft the manuscript. AR participated
in study design and data collection. GM participated in data collection and
helped with statistical analysis. LG participated in study design, interpretation
of data and helped to draft the manuscript. All the authors read and approved
the final manuscript.
Acknowledgements
Preliminary results were presented at the 21st Annual Meeting of the European
Society of Intensive Care Medicine (ESICM), held in Lisbon (Portugal) in 2008.
List of participating centers (all in Italy, unless otherwise stated): Centro Nazionale
di Informazione Tossicologica, Fondazione IRCCS Salvatore Maugeri, Pavia;
Fondazione IRCCS - Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena,
Milano; Ospedale di Faenza, Ravenna; Ospedale di Manerbio, Brescia; Ospedale
di Sondrio; Ospedale di Vimercate; Ospedale Maggiore di Novara; Ospedale
Maggiore Niguarda, Milano; Ospedale San Gerardo Nuovo dei Tintori, Monza;
Ospedale San Paolo, Milano; University College Hospital, London, UK; University
Hospital Zurich, Switzerland.
Author Details
1Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena
di Milano, Università degli Studi di Milano, Via F. Sforza 35, 20122 Milan, Italy,
2Ospedale San Gerardo Nuovo dei Tintori, Università di Milano-Bicocca, Piazza
dell'Ateneo Nuovo 1, 20126, Milan, Italy, 3Centro Nazionale di Informazione
Tossicologica, Fondazione IRCCS Salvatore Maugeri, Via Maugeri 10, 27100
Pavia, Italy, 4Bloomsbury Institute of Intensive Care Medicine, University
College London, 5 University Street, London WC1E 6JF, UK, 5University Hospital
Zurich, Rämistrasse 100, 8091 Zürich, Switzerland, 6Ospedale Niguarda Ca'
Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy and 7Ospedale San
Paolo, Università degli Studi di Milano, Via A. Di Rudiní 8, 20142 Milan, Italy
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