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Dynamic Parameters do not Predict Fluid Responsiveness in Ventilated Patients with Severe Sepsis or Septic Shock-Juniper Publishers

Abstract
The dynamic parameters, stroke volume variation (SVV) and pulse pressure variation (PPV), are used to guide fluid resuscitation in ventilated patients. We investigated whether SVV, PPV and pleth variability index (PVI), an automatic measurement of the plethysmographic waveform amplitude changes, can be used to predict fluid responsiveness in ventilated patients with severe sepsis or septic shock. We measured cardiac index, (CI, transpulmonary thermodilution PiCCO2) SVV, PPV, global end-diastolic index (GEDI), central venous (CVP), arterial blood pressure and PVI (Masimo Radical 7) before and after infusion of 500ml Gelofusine® over 30min in 31 deeply sedated ventilated patients (tidal volume 8ml/kg) with severe sepsis and septic shock. We obtained one full set of measurements in 30 patients. 10 patients increased CI by at least 15% ("responders”), 20 patients were "non-responders”. Baseline haemodynamic variables were not significantly different between both groups. The area under the receiver operating curves (mean, SE) were 0.68 (0.11) for SVV, 0.66 (0.12) for PPV, 0.59 (0.12) for PVI, 0.55 (0.12) for GEDI and 0.75 (0.09) for CVP We concluded that none of the investigated dynamic parameters could reliably predict fluid responsiveness in ventilated patients with severe sepsis and septic shock in our study.

Introduction

Shock in sepsis results from vasodilatation and a reduction of effective intravascular volume. Its treatment, among others, includes optimal fluid resuscitation. Both over and under resuscitation can worsen outcome in these patients [1]. Routine clinical examination and static indicators of cardiac preload such as central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), or left ventricular (LV) end diastolic area, are poor predictors of fluid responsiveness [1,2]. Recent studies have shown that respiratory variations in the dynamic indicators of LV stroke volume (SV), namely pulse pressure variation (PPV) and SV variation (SVV) are more reliable predictors of fluid responsiveness in ventilated septic patients [3-5]. Respiratory changes in the amplitude of the plethysmographic pulse wave (ΔPOP) have been shown to be as accurate as PPV in predicting fluid responsiveness in ventilated septic patients [5]. Pleth variability index (PVI), an automatic and continuous monitor of ΔPOP, has been demonstrated to predict fluid responsiveness in ventilated patients undergoing general anaesthesia [6], and in critically ill ventilated patients with circulatory insufficiency [4]. However, it is unclear whether PVI specifically predicts fluid responsiveness in ventilated patients with severe sepsis or septic shock. Therefore, we conducted a prospective, non-randomised, nonblinded observational study to compare the ability of multiple dynamic and static cardiovascular parameters to predict fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock.

Materials and Methods

The study protocol for this observational study was approved by both national and local ethics committees and was conducted in accordance with the Declaration of Helsinki of the World Medical Association. A valid informed and written consent was obtained from patients' next of kin, after detailed explanation of the protocol, prior to enrolment into the study. Retrospective consent was obtained from all patients who survived to discharge from intensive care and regained mental capacity.

Patients

Thirty-one adult non-pregnant patients who required sedation and controlled mechanical ventilation for treatment of severe sepsis or septic shock, as defined by the International Sepsis Definitions Conference [7], were enrolled in the study. Patients were subjected to a fluid challenge (500ml of Gelofusine® administered over 30min) if they showed at least one sign of inadequate tissue perfusion (systolic blood pressure less than 90mmHg, urine output less than 0.5mlkg- 1h-1 for more than 2 hours, tachycardia greater than 100 beats per minute or capillary refill greater than 2 seconds). Patients were sedated with a continuous infusion of Protocol and Alfentanil. Infusions were titrated to achieve a Richmond Agitation Sedation Scale of -3. Patients were ventilated with a pressure controlled mode (BIPAP mode, EVITA 4 XL, Draeger, Germany) with a tidal volume of 8ml/kg estimated ideal body weight and a positive end-expiratory pressure of not more than 15cm H20. Respiratory rate was adjusted to achieve an arterial partial pressure of CO2 of 4.8-6kPa. The FiO2 was titrated to achieve an arterial saturation of >92%, the ratio of inspiratory versus expiratory time did not exceed 1:1. Exclusion criteria included any spontaneous breathing activity, a known allergy to Gelofusine®, any cardiac rhythm other than sinus rhythm, contraindications for a fluid challenge (PaO2/FiO2 less than 13.3kPa, pulmonary oedema on chest X-ray), patients unable to lie supine or peripheral vasoconstriction causing obliteration of the plethysmographic signal.

Haemodynamic monitoring

Invasive haemodynamic monitoring was performed by using either a 20cm 5-Fr thermistor-tipped arterial thermodilution catheter (Pulsiocath, Pulsion Medical Systems AG, Germany) inserted into a femoral artery or by using a 22cm 4-Fr thermistor-tipped arterial thermodilution catheter (Pulsiocath, Pulsion Medical Systems AG, Germany) inserted into a brachial artery. The tip of a central venous catheter (Arrow International Inc., Reading, PA, USA) was positioned in the superior cava vein confirmed by X-ray examination. Central venous blood gas samples were taken pre and post fluid challenge (ABL 725, Radiometer, Copenhagen, Denmark). The arterial catheter was connected to an advanced haemodynamic monitor (PiCCO2®, Pulsion Medical Systems AG, Munich, Germany). Thermodilution was performed using at least three cold fluid boluses randomly throughout the respiratory cycle and was repeated within five minutes prior to and five minutes post fluid administration. The patient was positioned supine for all measurements. Electrocardiogram, arterial blood pressure, CVP and arterial oxygen saturation (SaO2) were continuously monitored (Spectrum Monitor, Datascope Corporation, Montvale, NJ, USA) and all recordings were taken at end-expiration. A pulse oximeter probe (LNCS® Adtx, Masimo Corp., USA) was attached to the index finger of the right hand and wrapped to prevent outside light from interfering with the signal. This pulse oximeter probe was connected to the Masimo Radical 7 monitor (Masimo SET, Masimo Corp., Irvine, CA, USA) displaying perfusion index and Pleth Variability Index (PVI).

Conduct of the study

After ensuring at least a 5-minute period of haemodynamic stability, the first set of measurements was obtained. This was followed by a fluid bolus of 500ml Gelofusine® infused intravenously over 30min. The second set of measurements was obtained 5min after the fluid infusion was completed. Ventilator settings and dosages of inotropic, vasoactive and anaesthetic drugs were held constant throughout the measurements. At each step of the protocol, the following variables were recorded: Heart rate (HR), systolic, diastolic and mean arterial pressure (MAP), CVP, central venous oxygen saturation (ScvO2), SV, SV index (SVI), CO, cardiac index (CI), global end-diastolic index (GEDI), SpO2, PPV, SVV and PVI. All patients were kept in a supine position during the entire period of the study. Only one full set of data was obtained and analysed per patient.

Statistics

In accordance with previous studies [8], we took the criteria of a 15% increase in CI in response to the fluid challenge to differentiate responders from non-responders to fluid. The normality of distribution of data was tested using the Kolmogorov-Smirnov test. Parametric data are presented as mean with standard deviation or standard error and non- parametric data as median with inter-quartile range (IQR).
We compared non-parametric haemodynamic data before and after volume expansion in responder and non-responder patients using the Mann-Whitney U test. Wilcoxon signed rank tests were used to compare the response to fluid in responders and non-responders, respectively. Receiver operating characteristic (ROC) curves comparing the ability of CVP, SVV, PPV, GEDI and PVI at baseline to discriminate between responders and non-responders to volume expansion were generated varying the discriminating threshold of each parameter. Using the results from previously published studies [3], we conducted a priori power calculation which showed that 31 patients were necessary to detect differences of 0.1 between areas under the ROC curves with a 5% two-sided type I error and 80% power. A p-value less that 0.05 was considered as significant. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 20.0.

Results

Thirty-one patients were recruited. One patient declined to provide consent retrospectively. Complete sets of data were analysed for the remaining 30 patients. Baseline characteristics, as well as respiratory variables and vasopressoinotropic requirements were not statistically different between responders and non-responders (Table 1). Ten patients increased CI by 15% or more after volume expansion and were classified as responders. 20 patients were classified as nonresponders. There was no statistically significant difference in any haemodynamic variable at baseline between the two groups (Table 2). Both responders and non-responders increased CVP and decreased PPV in response to the fluid challenge (Table 3 & 4). Only responders showed a statistically significant increase in GEDI (Table 3). Receiver operating characteristic curves (ROC) comparing the ability of CVP, SVV, PPV, PVI and GEDI to predict fluid responsiveness is shown in (Figure 1). The area under the receiver operating curves (mean, SE) were 0.68 (0.11) for SVV, 0.66 (0.12) for PPV, 0.59 (0.12) for PVI, 0.55 (0.12) for GEDI and 0.75 (0.09) for CVP (Table 5, Figure 1).
BSA: Body Surface Area; FiO2- Fraction of Inspired Oxygen; PEEP Peak End Expiratory Pressure; PaO2 Partial Pressure of Arterial Oxygen; PaO-2/ FiO2 Ratio of Partial Pressure of Arterial Oxygen with Fraction of Inspired Oxygen. Vasopressin and Adrenaline was used only in one patient each.
HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation.
HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation
HR: Heart Rate; MAP: Mean Arterial Pressure; CVP: Central Venous Pressure; SVRI: Systemic Vascular Resistance Index; GEDI: Global End Diastolic Index; CI: Cardiac Index; PPV: Pulse Pressure Variation; SVV: Stroke Volume Variation; PVI: Pleth Variability Index; ScvO2, central venous oxygen saturation.
AUC: Area Under the Curve; SE: Standard Error; CI: Confidence Interval; CVP: Central Venous Pressure; SVV: Stroke Volume Variation; PPV: Pulse Pressure Variation; PVI: Pleth Variability Index; GEDI: Global End Diastolic Index.
Discussion
This study aimed to compare the ability of PVI with the more established parameters PPV, SVV, and GEDI to predict fluid responsiveness in mechanically ventilated patients with severe sepsis or septic shock. The main finding is that none of the above haemodynamic parameters were able to reliably predict fluid responsiveness despite exclusion of common known confounding factors. We observed a significant number of false positive and false negative results considering previously cited cut-off values for dynamic parameters in general ICU and more specifically in ventilated septic patients [4,5,8-10]. Our study population consisted of ventilated patients with severe sepsis and septic shock. All but three patients were receiving vasopressor support. Known confounding variables affecting the ability of dynamic parameters to predict fluid responsiveness were excluded: all patients were in sinus rhythm during the study period and did not have any arrhythmia; all were deeply sedated without any spontaneous breathing activity and received a tidal volume of 8ml/kg estimated lean body weight. Haemodynamic measurements were performed using the PiCCO 2 monitor which is a well validated accurate monitor measuring SV even in rapidly changing circulatory conditions [11] and in patients with reduced cardiac function [9]. At least three cold boluses were given randomly throughout the respiratory cycle using the same sampling period (30 seconds) to obtain relevant haemodynamic data using transpulmonary thermodilution [12]. In line with other studies, we used a fluid bolus of 500ml Gelofusine® administered over 30min [5]. The mean CVP increased after volume expansion in both responders and non-responders by at least 2mmHg (Table 3 & 4), which has been defined previously as a proof for an adequate fluid challenge [13]. We explored the possible reasons for the unexpected finding that none of the dynamic parameters reliably predicted fluid responsiveness in our study. Less than 50% of our patients were responders. This is not uncommon in critically ill patients with severe sepsis/septic shock or after cardiac surgery [10,14,15]. It is known that septic shock is frequently associated with biventricular dysfunction and increased pulmonary artery pressure [16]. Both RV and LV failure are well known confounders altering the magnitude and ability of PPV and SVV to predict fluid responsiveness [17]. Impaired RV function is also a frequent problem in ARDS, a condition commonly associated with septic shock [18]. In case of RV dysfunction/failure, one might observe "false" high PPV and SVV in non-responders as the RV after load, in contrast to preload change, is the major determinant for high PPV and SVV [14,19]. This could be further exacerbated by increased pulmonary artery pressure, large tidal volumes and high PEEP [18,20], the latter two of which were present in our study (Table 1). Previous studies on the ability of dynamic parameters to predict fluid responsiveness in septic patients either did not measure pulmonary artery pressure [5], pulmonary artery pressure was not significantly raised [3] or PEEP values were low [10]. In our study, all but three patients received vasopressors, which can independently increase pulmonary artery pressure. Daudel and colleagues demonstrated that, in contrast to haemorrhagic shock, in endotoxemic shock with raised pulmonary artery pressure, PPV did not predict fluid responsiveness [19]. A similar conclusion was reached by VanBallmoos who reported a reduced RV ejection fraction in almost half the non-responders and in none of the responders in patients with septic shock or post cardiac surgery [14].
In case of LV dysfunction/failure both PPV and SVV are generally decreased [3,17]. However, Mesquida et al have shown that if PPV and SVV are being used for fluid resuscitation in heart failure conditions, the phase relation between airway pressure and the maximal SV and hence PP needs to be determined [17]. If the LV is afterload dependent, one could observe a simultaneous increase in SV and hence PP when intrathoracic pressure increases and thus PPV and SVV might be high without reflecting fluid responsiveness particularly if the tidal volume is high and/or the chest wall is stiff e.g. due to sepsis induced oedema. For the haemodynamic measurements taken by the PiCCO system the phase relation between the change in airway pressure and maximal PP and SV is unknown. PPV and SVV are calculated over a 30sec rolling period. Reuter et al reported that SVV measured by the PiCCO system is still a reliable marker of fluid responsiveness in LVF with EF<35% [9]. However, in this study the AUC for SVV to predict fluid responsiveness in patients with impaired LV function was 0.76 which was lower than the AUC for SVV to predict fluid responsiveness in a second group of patients with normal LV function (0.88).
Gruenewald et al reported that in animals suffering from stunned myocardium shortly after cardiac arrest all dynamic parameters are unreliable in predicting fluid responsiveness [21]. Wiesenack and colleagues, found no correlation between SVV measured by the PiCCO system and prediction of fluid responsiveness in patients undergoing elective coronary artery bypass surgery, with an ejection fraction >50% [22]. In this study the authors speculated that arterial pulse contour- derived estimates of SVV are potentially unreliable under positive pressure ventilation. PPV is considered the more sensitive and specific parameter compared to SVV in predicting fluid responsiveness as pressure measurements are usually more accurate than SV measurements. However, in our study neither baseline SVV nor PPV could reliable predict fluid responsiveness. SV and PP are tightly correlated during positive pressure ventilation [17]. The magnitude of PP for any given SV depends on central arterial compliance. Thus, a vasopressor induced reduction in central arterial compliance could lead to large changes in PP and hence PPV even for small changes in SV. The majority of the patients in our study were treated with vasopressors and it is tempting to speculate that this might be a further explanation why some patients were unresponsive to fluids despite high baseline PPV. Furthermore, it is conceivable that a more pronounced inspiratory increase in PP is due to an exaggerated dUp phenomenon in the presence of reduced LV function [8]. which might have contributed to an increase in PPV in non-responders.
As the cyclic changes in RV and LV pre- and after load are dependent on cyclic changes in intraalveolar, intrapleural and hence transpulmonary pressure any factor affecting one or a combination of these would have an impact on all dynamic parameters. Increasing tidal volume directly increases the magnitude for PPV and SVV for any given chest and lung compliance [17]. Intraabdominal pressure affects chest wall compliance and hence intrapleural pressure. In fact, Jacques et al showed that the cut-off values for all dynamic parameters increase significantly if intraabdominal pressure is increased [23]. We did not measure intra abdominal or intrapleural pressure in our study. Respiratory system compliance was not significantly different in both groups. However, we cannot exclude the possibility that differences in transpulmonary pressures induced by the same tidal volumes might have contributed to our findings. Loupec et al showed that PVI reliably predicts fluid responsiveness in critically ill ventilated patients [4]. However, this result has not always been replicated in septic patients treated with vasopressors [10,15,24]. One possible explanation for this finding could be that the proportion of septic shock patients was lower in Loupec's study (55%) than in the other studies (85%, 86%) [4,10,15].

Conclusion

We conclude that the dynamic parameters PPV, SVV and PVI may not be able to predict fluid responsiveness in all ventilated patients with severe sepsis or septic shock even after exclusion of already commonly known confounding factors. An assessment of RV and LV function and measurement of intraabdominal or even transpulmonary pressure should be taken into account before interpreting and acting on the values measured. Passive leg raising, as a "reversible” fluid challenge might help to prevent unnecessary and potential harmful fluid loading provided intraabdominal pressure is not increased [25].

Acknowledgement

Hardware and software for the conduct of the study were supplied by Masimo Corp., Irvine, CA, USA.
The study was supported by a grant from the Research Development Department, The James Cook University Hospital, Middlesbrough, United Kingdom.
For more Open Access Journals in Juniper Publishers please click on: https://juniperpublishers.com
For more articles in Journal of Anesthesia & Intensive Care Medicine please click on: https://juniperpublishers.com/jaicm/index.php
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A rough overview of employment in Toronto's life sciences sector.

Here is a profile of the life sciences sector in Toronto, focusing on laboratory occupations. It’s shocking how little even job counsellors in employment services know about the sector. I’m no guru, but these people don’t even know the differences between related positions. Figured I may as well and make something useful out of my continued failure to make my degrees useful. This is heavily biased towards biomedical laboratory research, but I have tried to include other fields of biology such as ecology. There are some healthcare and teaching occupations listed here, but I feel those sectors would be better analyzed by someone else who knows them and deserve their own profiles. The National Occupation Classification or NOC also maintains this separation by having healthcare occupations begin with 3 and education with 4, as opposed to 2 for natural sciences. Also excluded are positions which are primarily managerial, business, sales, or manufacturing trades (as opposed to technicians): these NOCs start with 0, 1, 6, and 9, respectively.
These listed organizations that have a heavy focus on life science (excluding certain sectors like food and cosmetics) are based in Canada (unless otherwise stated) and appear if I’ve seen a GTA-based posting of any of the positions listed here from the organization at least once since I started job searching in 2016. This criterion hopefully means that the organizations listed here are actively hiring, at least on a timescale that thinks 5 years ago is “recent”. This obviously does not include hidden jobs as this write-up is based on (mostly) transparent, publicly-available sources. The best job boards in terms of accessing organizational postings seem to be Indeed (widest net) and Eluta (local positions). This is not advertising for any company, so links are provided only if they provide additional information related to the jobs they offer. I welcome any additional contributions for things where I have little knowledge. And I hope this may inspire others to write about other industry sectors in Toronto to aid young people graduating from school and trying to establish a career in the post-Great Recession milieu.
 
Let’s begin with an overview of the life sciences sector in Toronto according to a number of reports, available online as PDFs, in the grey literature. The latest one (though it cites 2016 and earlier sources) is the 2019 report published by the industry association Life Sciences Ontario. The concentration of the industry in the Greater Toronto Area means the impressions here are that of life sciences in Toronto as well. This industry that generates billions of dollars and thousands of jobs is mostly dominated by small (less than 10 employees) and medium (less than 100) enterprises. A 2016 Toronto Region Human Health and Sciences Cluster Action Plan reiterates these facts for the GTA itself in addition to marking out oncology, cardiology, and neurology as strengths.
The Ontario Bioscience Innovation Organization’s 2016 Industry Engagement Report, while acknowledging advantages such as a high proportion of university graduates, mentions weaknesses of the industry such as low investment capacity within Canada, with most funding being from public sources. The industry perspectives shown reveal that companies think “there are too many co-op and ‘new grad’ programs”, hinting at how useful these university programs really are, as the main hiring challenge for these companies is filling senior positions. This also potentially suggests a general unwillingness to invest in training their workforces, which is actually stated in the 2013 BioTalent Canada Labour Market Information Report. According to this document, firms in the report also tend to outsource talent requirements to other organizations in the GTA, Canada, US, and then from abroad. When they do recruit people into their workforces, they prefer to use informal methods such as personal contacts and employee referrals. One needs connections to have a good chance of securing a job in the industry.
 

Healthcare

Hospitals and other organizations that focus on providing care to patients.
Research Hospitals
These hospitals, mostly found in the downtown area, maintain research institutes with close connections to universities such as U of T.
  • St. Michael’s Hospital The odd one out of the downtown hospitals, being right next to the Eaton Centre. Most of its research activities are in the Li Ka Shing Knowledge Institute across Shuter. It has research programs in injury care, neuroscience, cardiovascular disease, orthopedics, imaging, urban health, and global health.
  • Hospital for Sick Children (Sick Kids) With an eye towards children’s health, their main research programs are in the fields of cellular biology, developmental biology, genome biology, molecular medicine, neuroscience, translational medicine, and health evaluative services.
  • University Health Network (UHN) The largest medical research network in Toronto, spread over a number of hospitals and research institutes. Most of the institutes are localized to a particular hospital, with the exception of the McEwen Stem Cell Institute at MaRS.
    • Toronto General Hospital (TGH) Home of the Peter Munk Cardiac Centre, TGH’s research specialties include cardiovascular disease, organ transplantation, regenerative medicine, infectious diseases, autoimmunity disorders, psychosocial care, and health systems.
    • Princess Margaret Hospital Specializes in cancer with its titular Princess Margaret Cancer Centre, with subspecialties in cancer imaging, computational medicine, genomics, immuno-oncology, structural biology, stem cells, and supportive care.
    • Toronto Rehabilitation Institute KITE conducts research in the areas of prevention, restoration, enhanced participation and independent living.
    • Toronto Western Hospital One of the major research hospitals outside the downtown core. The Krembil Research Institute focuses on research regarding diseases of the central nervous system, skeleton, and eyes.
  • Mount Sinai Hospital The Lunenfeld-Tanenbaum Research Institute has programs in molecular biology, stem cells, cancer genetics, metabolism, neurodevelopment, precision medicine, and population health.
  • Sunnybrook Health Sciences Centre The other major research hospital found way beyond downtown, over near Bayview and Eglinton. They have programs for brain, heart, cancer, trauma, orthopedics, rehabilitation, obstetrics, and veteran’s health.
  • Holland Bloorview Kids Rehabilitation Hospital Its research centre focuses naturally on childhood disabilities, both mental and physical.
  • Baycrest Health Sciences The Rotman Research Centre focuses on the elderly brain, with [programs] dedicated to cognition, aging, dementia, and computational biology.
  • Center for Addiction and Mental Health (CAMH) Toronto’s premier psychology research organization has three campuses at College, Queen, and Russel Streets. Their programs concern basic research, brain imaging, computational approaches, brain stimulation, personalized medicine, adult disabilities, youth issues, and public policy.
Health Services
  • Lifelabs Chain of diagnostic labs, possibly the largest in the GTA.
  • Dynacare Another chain offering diagnostic services, based in Brampton.
  • CReATe Fertility Centre Downtown fertility clinic.
  • CHARM Fertility Fertility clinic in Etobicoke.
 

Positions

Most research positions in the biological sciences correspond to NOC 2121 (“Biologists and related scientists”).
  • Lab/Research Technician/Technologist Typically works in research labs. On paper the minimum is a B.Sc. but in practice prefers higher degrees with considerable experience (bare minimum of 1 year, more for higher grades), especially in specialized techniques such as flow cytometry. Animal handling positions may sometimes be a more specialized Animal/Veterinary Technologist/Technician (NOC 3213) position, requiring a veterinary degree. Note that this position is not the same as a Medical Laboratory Technician position (NOC 3211) that requires certifications.
    With the increasing emphasis on data-driven approaches, computational and mathematical skills and experience are becoming crucial. Bioinformaticians have increased specializations in statistical approaches, requiring degrees in mathematics or computer science. Knowledge of programming languages (e.g. Python) and software (e.g. R, MATLAB) is valuable. Microbiologists focus on microorganisms, especially pathogens, and as such also find employment in food product manufacturers.
  • Research Assistant While similar to Research Technicians, Research Assistants are typically more involved with clinical studies involving human subjects. Requirements are somewhat lesser, with a three-year college degree being acceptable, but at least 1 year of experience is generally required.
  • Laboratory/Research CoordinatoManager Typically work in either larger lab groups or oversee core facilities shared by groups of researchers. They use their technical expertise to assist other members of research groups in specialized techniques/equipment. Requires post-secondary degrees and 2-7 years of experience.
  • Staff Scientist/Biologist/Primary Investigator Run their own research laboratories and are typically cross-appointed to university life science departments. Requires at least a Ph.D. with a strong publication record.
 

Education

In addition to providing degrees in the life sciences, their departments also run research programs that constitute the traditional career routes of academia.
Universities
  • University of Toronto Has campuses downtown, Scarborough, and Mississauga. Co-op degrees are only offered at the Scarborough campus, where life science courses are run by the Department of Biological Sciences. The Mississauga campus has its own Department of Biology. The downtown St. George campus has a variety of life sciences programs run departments in the Faculty of Medicine and Faculty of Arts and Sciences.
  • York University While the smaller Glendon campus has its own biology program, the bulk of the teaching and research is at the larger Keele campus. The Faculties of Science, Health, and Environmental Science contain Keele’s life science departments. Life sciences constitute the first batch of York co-op programs.
  • Ryerson University Offers biology programs through the Department of Chemistry and Biology, which offers co-op programs.
Colleges
  • Centennial Has a number of campuses in Toronto, but the life science (biotech, environment) programs are taken at the Scarborough Morningside campus.
  • Humber Based in Etobicoke with a Lakeshore campus. Life sciences are covered under Health & Wellness programs.
  • Seneca Campuses in North York and one downtown with biotech and environmental programs.

Positions

The occupations mainly fall under the NOC 4011 (“University professors and lecturers”, also includes postdoctoral positions) and previously-mentioned 2121. Most of the positions listed here form the post-graduate path of academia, at the end of which is the treasured tenured professorship.
  • Lab Technician While often similar to the research technician positions in hospitals (NOC 2121), some of these positions are designated instead by NOC 4012 (“Post-secondary teaching and research assistants”). These techs work in teaching labs with more routine setting up of hands-on exercises for students.
  • Postdoctoral Fellow Usually abbreviated as “postdoc”, the name indicates this is the next step in the academic ladder after getting your Ph.D. Unlike graduate school, the recruitment is more formal and the successful candidate is expected to carry out research projects mostly independently, with only oversight instead of supervision from the lab’s primary investigator. In addition to the doctorate, a great publication record is necessary to secure these positions.
  • Research Associate A more senior position, they typically require around 4-6 years of postdoctoral or related experience along with an excellent published portfolio and knowledge of specialized techniques. In larger labs, research associates may be in charge of subdivisions, possibly even managing projects and supervising others.
  • Professor The coveted goal of the academic research path, accessible only after years of schooling and research and often not even after that. There are several levels, from Assistant Professor to Associate Professor, and then just full professor. Tenure is typically only available at the later stages. A very strong publication record gained from successful, high-profile postdoc and higher positions is a prerequisite.
 

Pharmaceuticals

The largest constituent of the private sector in Toronto’s life science community, these companies manufacture and distribute products used in healthcare. Drug companies in Canada have been affected by the same trends that apply to the industry worldwide, particularly increased cost pressures that force companies to streamline operations. Increased manufacture of biologics (large molecules derived from organisms as opposed to small, synthesized ones) provides an opportunity for those with a biology as opposed to chemistry background. Parts of operations have been outsourced to outside companies like testing labs and CDMOs (Contract Development and Manufacturing Organizations, see Lab Services subsection for examples).
Majors
Multinational companies with revenue in the billions. Most of their facilities are on the outskirts of or just outside Toronto.
  • Sanofi Pasteur The vaccine division of the French pharmaceutical company Sanofi has sites in North York (manufacturing facility) and in Mississauga (office for Genzyme subsidiary).
  • Eli Lilly A US pharmaceutical concern with a recently closed Scarborough facility, now located downtown.
  • Johnson and Johnson American corporation with offices in Markham (consumer and medical products) and North York (medicines under the Janssen banner).
  • GlaxoSmithKline A British pharmaceutical company with a Mississauga manufacturing facility and head office.
  • Amgen American biotech firm with an office in Mississauga.
  • Bayer This German company has a corporate office in Mississauga.
  • Roche Swiss company with an office in Mississauga.
  • AstraZeneca European pharmaceuticals concern with a corporate office in Mississauga.
  • EMD Serono The North American subsidiary of the German company Merck has a Mississauga office.
  • Purdue This US pharmaceutical’s Canadian division is based at a facility in Pickering, which is apparently closing mid-2020 according to onlyhalalporkallowed.
  • GE Healthcare US medical equipment and systems provider with a Mississauga facility.
Minors Includes many start-ups, many of which are located at the MaRS incubator located downtown close to U of T.
  • Mediphage Bioceuticals Gene therapy company based at MaRS.
  • BlueRock US cell therapy company with lab space in MaRS.
  • Deep Genomics Computational drug discovery at a lab in MaRS.
  • Geneseeq Applies advanced sequencing techniques for cancer at MaRS.
  • Telo Genomics Telomere analytics at a MaRS lab.
  • Ranomics Provides genetic analysis tools from its MaRS lab space.
  • Inagene Diagnostics Personalized medicine genetics at a midtown laboratory.
  • Luminex American molecular diagnostics company with a downtown lab.
  • Vital Biosciences Personalized diagnostics in Mississauga.
  • Therapure Biopharma Protein therapeutics company with Mississauga factory and office/warehouse.
  • Microbix Manufacturing of viral and bacterial products at a Mississauga facility.
  • Theralase Produces laser treatment devices at a facility just west of Scarborough.
  • ANGLE Biosciences Develops cancer diagnostic devices at its Etobicoke facility.
  • Fluidigm American microfluidics company with manufacturing facility in Markham.
  • Baylis Medical device firm with office/production in Mississauga.
  • Qvella Diagnostic devices company with headquarters/production facility in Richmond Hill.
  • Baxter US medical device firm with Mississauga office and manufacturing site.
Generics
Manufacture pharmacologically-similar copies of drugs that have expired patents.
  • Apotex Largest generic drug company in Canada. Multiple facilities with additional functions in the GTA: North York (headquarters), Etobicoke, and Richmond Hill (warehouse).
  • Teva Canada Subsidiary of the major Israeli generics manufacturer, it has facilities in Scarborough (main office and logistics centre) and Markham (antibiotics production).
  • Leo The Danish company’s Canadian subsidiary has a facility in Markham.
 

Positions

Laboratory and production occupations in pharmaceuticals mainly fall under NOCs 2221 ("Biological technologists and technicians") and 2233 (“Industrial engineering and manufacturing technologists and technicians”). Office positions here fall under NOC 1122 (“Professional occupations in business management consulting”).
  • Intern True entry-level positions that require nothing more than one be currently-enrolled in the degree related to the job. Experience requirements for most positions in pharmaceutical companies make these absolutely essential.
  • Quality Assurance/Control Ensures procedures and products abide by the common Title 21 Code of Federal Regulations pharmaceutical standard used by the US Food and Drug Adminstration. Requires 5-10 years of experience in testing and investigations.
  • Production Technician Usually divided into upstream (raw materials) and downstream (production line) specializations. Requires a science degree and 1-3 years of industry experience depending on the grade. Recent experience is valuable due to rapid changes in methods such as the emergence of continuous manufacturing.
  • Scientist Usually involved in manufacturing as a senior qualified expert. Requires a postsecondary degree and 2-4 years of pharmaceutical industry experience.
  • Medical Advisor A degree and 2-5 years in the pharmaceutical industry are recommended. Bilingualism is ideal.
  • Regulatory Affairs Associate In addition to a degree, one ideally also has a certificate in regulatory affairs and 1-2 years of drug company experience, especially with Health Canada submissions. A recent global trend in regulatory harmonization makes this position a crucial one for pharmaceutical firms.
  • Document Reviewer A life science B.Sc. and 2 or more years of pharmaceutical experience are needed.
 

Other

Government
  • Ontario Institute for Cancer Research Institute funded by the province based at MaRS, with programs focusing on cancer monitoring, translational medicine, and drug development.
  • Public Health Ontario Operates a network of laboratories across Ontario that perform testing services to support public health maintenance. The Toronto location is at MaRS.
  Lab Services
Mainly serve the pharmaceutical industry, though some offer their services to consumers as well.
  • Nucro-Technics A testing lab in Scarborough.
  • Eurofins Luxembourgish laboratory analysis chain with locations in downtown, Markham, and Missisauga.
  • Canadian Analytics Laboraties Mississauga drug and cosmetics analysis lab.
  • EMC Scientific Environmental testing lab in Mississsauga.
  • Diteba Operates testing laboratory in Mississauga.
  • SGS Swiss verification and certification company with labs in North York, Markham, and Mississauga (also has offices).
  • Everest Clinical Research Headquartered in Markham.
  • Lambda Therapeutic Research Indian clinical research firm with Scarborough facility.
  • Dalton Pharma Services CDMO offering drug discovery and manufacturing services, based in North York.
  • Thermo Fisher Scientific US-based laboratory supplies and equipment manufacturer with an office in Mississauga.
  Consulting
Most are in the field of environmental planning, especially for engineering projects.
  • Pinchin Mississauga head office with downtown branch.
  • Amaris French consulting firm with an office downtown whose life sciences division is focused on manufacturing.
  • Dillon Has an office in North York.
  • Wood PLC British multinational with offices in Toronto and Mississauga.
  • AECOM American firm with branches in Mississauga, Markham, and Vaughan.
  • Stantec Offices in Toronto, Markham, and Mississauga.
  Environmental
Organizations with a primary focus on environmental work, other than municipal governments themselves.
  • Toronto and Region Conservation Authority Head office in Vaughan.
  • Credit Valley Conservation Authority For Mississauga region.
  Miscellaneous
  • Toronto Zoo Aside from exhibits, they also have wildlife conservation initiatives.
  • Ripley’s Aquarium
  Staffing Agencies
  • Kelly Services Its scientific division covers a variety of life science fields such as biotech, pharma, and environment.
  • PIVOTAL Has a narrower focus, mainly in pharmaceuticals.
 

Positions

  • Field Application Scientist Provides support for specialized techniques provided by laboratory supplies. Requires a life sciences degree and at least 3 years of experience.
  • Ecologist NOC 2121. Engages in field work in support of environmental services. Requires a related degree, at least 3 years of related experience, outdoor certifications, and a driver’s license. Related are Aquatic/Fisheries specialists and Risk Assessors (requires at least 2 years of field experience).
  • Arborist/Nursery Technician Covered by NOC 2225 (“Landscape and horticulture technicians and specialists”).These tree-care professionals need a related degree and at least 3 years of experience. Licensing, if required, is covered by the Ontario College of Trades.
 
What can we conclude from looking at these various organizations and positions? To be an excellent candidate a life sciences student should focus on securing many internships that grant valuable experience. In addition, these also cultivate connections, the one merit to rule them all and in the hiring process select them. Co-op work terms are not sufficient to make one competitive, given how common these programs have become. The primacy of smaller organizations that are incapable or unwilling to use proper formal selection processes means networking is absolutely key in this industry. Education must be focused on obtaining key mathematical, statistical, and computational qualifications, along with experience in specialized procedures. Why various levels of government here tolerate such severe mismatches between students’ skills and position requirements while continuing with policies that create an oversupply of graduates in fields with global competition (see Appendix C) is an important question that needs to be answered.
 

Appendix A: Specialized qualifications for life science positions.

If the people working at a certain lab publish results, reading their papers is a good way to ascertain if they use the tools laid out in this appendix.
Laboratory Techniques
Working in labs that use these specialized techniques gives experience that is in demand.
  • Flow cytometry A technique for analyzing and sorting cells via a stream of liquid and laser optics.
  • Animal handling Generally rodents, though some labs use more exotic options like zebrafish.
  • Protein purification Comprises a number of procedures, from expressing proteins in models like bacteria or yeast, all the way to the use of various chromatography procedures to isolate the fraction the protein is in.
  • Next-generation sequencing A method of sequencing genetic material that relies on a massively parallel procedure to ensure fast reads, it is the workhorse of genomics in this day and age.
  • qPCR A Quantitative implementation of the Polymerase Chain Reaction amplification technique allows for the enumeration and analysis of gene expression profiles.
Computational Tools
The current trend in the life sciences has been for the use of computers to analyze large data sets. These languages, platforms, programs, etc. are very important qualifications in the current era.
  • Python This general-purpose programming language finds a lot of use in the sciences, and is often required for computational biology positions.
  • Perl Another general-purpose programming language that is an alternative to Python.
  • SQL Widely-used language for databases.
  • R A programming language and software program for statistics which appears to be the most popular. This may be due to it being free software compared to proprietary packages like SAS and SPSS.
  • MATLAB A proprietary programming language and software package used for mathematical operations and visualizations.
  • LIMS Laboratory Information Management Systems are programs that keep track of various lab operations such as inventory and databases. Industry positions may make use of related enterprise software such as SAP.
  • Linux Due to its open-source status, this operating system finds use in some labs.
 

Appendix B: Selecting a lab to work at.

Aside from the techniques mentioned in Appendix A, there are other factors to consider in selecting a laboratory for your internship/co-op work term/grad school. Reading published papers also reveals their collaborators, which is an indicator of the probably connections you'd make by working at said lab. The other means of gathering information on the suitability of a lab is a tour, usually done if you are interviewing with a potential supervisor. By looking at their facilities and talking to the other members, you can glean more about the methods available in the lab as well as how people get along in this prospective workplace. An important consideration is the supervision style of your superior, and whether it might not be the best fit for how you do things (e.g. a hands-on supervisor with an independent-minded student).
 

Appendix C: Canadian immigration programs for life sciences workers.

The vast majority of the positions here require skilled workers, accessible to newcomers primarily via the federal government’s Express Entry permanent residence program. Potential applicants are prioritized based on language, education, experience, age (18-35), and offers of employment. The different programs that comprise Express Entry share the basic overall process and requirements for the employers. Of particular note to job seekers is that these positions must pay at the minimum the median wage given by Job Bank. These positions must also be advertised on Job Bank or alternative methods for a few weeks.
After the employer has gone through this process and there have been no suitable Canadian candidates, they must then file a Labour Market Impact Assessment (LMIA) which proves the need for newcomers. LMIAs are then either approved or denied based on the circumstances of their filing. Programs that require an LMIA include the Federal Skilled Worker Program and the Canadian Experience Class (as the name indicates, the candidates already have legal work experience in Canada). The last Express Entry program relevant to the life sciences that uses the LMIA are the Provincial Nominee Programs.
The Ontario Immigrant Nominee Program is based on the Ontario Immigration Act 2015. The streams involved have the usual education and qualification requirements in addition to various requirements such as settlement funds (or an equivalent job offer), intent to reside in Ontario, and recent residency in Ontario. Streams that affect the local life sciences sector are the Employer Job Offer (Foreign Worker, International Students) and International Graduate (Master’s and PhD) streams. As of the time of this writing (March 2020), only the PhD stream is open for applications.
Quite a few Express Entry programs are exempt from the LMIA requirement. The International Mobility Program covers various things such as agreements signed by Canada (e.g. free trade agreements with movement of labour provisions) and sectors considered to be “Canadian interests” (relevant ones include postdocs and co-ops, the latter via the International Experience Canada program). The Post-Graduation Work Permit Program covers international students who have finished their Canadian programs, allowing them to obtain Canadian work experience. Global Skills Strategy allows companies to hire top talent in an expedient manner, LMIA-exempt for the life sciences which require university degrees.
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