We are privileged to be hosting the first of 4 articles all about the minefield that is, ‘Fluid therapy in the critically ill’! They were all written by Manu Malbrain (a good friend of mine), who is an internationally renowned expert in this complex field.
If you work your way through all 4 articles, you will find you have built yourself a fairly advanced understanding of the pearls and pitfalls of IV therapeutics. What strikes me regarding this, the first, is that it certainly is not simple and does require in depth understanding of complex physiology, (hampered by pathological processes), as well as skill in the utilisation of complex monitoring modalities. It is also apparent that it takes a substantial amount of time and dedication to do this properly. We are all so busy, and within times where resources and staff ever dwindle (UK particularly), it is no surprise that most of us struggle to follow what is clearly the gold standard set here!
We commend Manu and his colleagues for sharing their experience and expertise to bring us this series.
A final note, we hope to see you all at iFAD 2017 (Antwerp). Bound to be an amazing meeting.
Introduction and background
Preload and fluid responsiveness are two different things. In certain situations, like patients with increased intrathoracic pressures, traditional barometric filling pressures (eg central venous pressure and pulmonary artery wedge pressure) are erroneously increased. In those circumstances volumetric preload indices better reflect the true preload conditions of the patient. Fluid management in these patients can be very tricky because early adequate initial resuscitation is mandatory however in order to prevent organ edema and secondary abdominal hypertension one must avoid ongoing futile fluid loading. We will illustrate opposite changes between barometric and volumetric preload indices in a patient with increased intrathoracic pressure.
Patients and Methods
The case of a 26-year-old man admitted to the ICU after general seizures described. This case was presented and multiple-choice questions were presented to the delegates via an interactive voting system at the 32nd annual international symposium on intensive care and emergency medicine (ISICEM) in Brussels on March 20th 2012, at the 2nd International Fluid Academy Day (IFAD) in Antwerp on November 17th 2012, and at the 33rd annual ISICEM precongress symposium course on abdominal problems in Brussels on March 18th 2013.
In this patient, who developed shock within 18 hours of ICU admission the dynamic evolution is presented. Despite initial normal (and thus adequate) filling pressures, further fluid resuscitation was needed to overcome the ebb phase (this was guided by functional hemodynamic parameters and volumetric preload indices). Diuretics were initiated after 24 hours to help the patient to transgress to the flow phase because of respiratory failure due to capillary leak as evidenced by increased extravascular lung water.
This case nicely demonstrates the biphasic clinical course from ebb to flow during shock as well as the inability of traditional filling pressures to guide us through these different phases. It also illustrates and provides answers to the four basic but crucial questions that need to be solved in order to avoid harm: 1) when do I start giving fluids, 2) when do I stop giving fluids, 3) when do I start fluid removal, and finally 4) when do I stop fluid removal?
Preload and fluid responsiveness are two different things [1-3]. In certain situations like patients with increased intrathoracic pressure (ITP) related to increased intra-abdominal pressure (IAP) or the use of high positive end expiratory pressures (PEEP) during lung protective ventilation, traditional barometric filling pressures like the central venous pressure (CVP) or pulmonary artery wedge pressure (PAWP) are erroneously increased [4, 5]. In those circumstances, volumetric preload indices like global end diastolic volume index (GEDVI) obtained with transpulmonary thermodilution, right ventricular end diastolic volume index (RVEDVI) obtained via Swan-Ganz pulmonary artery catheter (PAC) or left ventricle end diastolic area index (LVEDAI) obtained via transthoracic echocardiography better reflect the true preload conditions of the patient. Since increased ITP has an impact on the global ejection fraction (GEF), correction of GEDVI in relation to the GEF may further improve the predictive value of this preload parameter . Fluid management in these patients can be very tricky because early adequate initial resuscitation is mandatory however in order to prevent secondary intra-abdominal hypertension (IAH) one must avoid ongoing futile (crystalloid) fluid loading [7-11]. We will illustrate opposite changes between CVP and GEDVI in a patient with increased ITP related to acute respiratory failure with pulmonary hypertension and a transiently opened foramen ovale .
This blog post dealing with “The 4 questions of fluid therapy” is the first in a total series of four, the others being:
- “The 4 D’s of fluid therapy”
- “The 4 indications for fluid therapy”
- “The 4 phases of fluid therapy”
What are the risks of fluid overload?
When considering fluid therapy and administration 4 basic questions need to be taken into account:
- When to start giving fluids (what are the benefits of fluid administration)
- When to stop giving fluids (what are the risks of ongoing fluid administration)
- When to start removing fluids (what are the benefits of fluid removal)
- When to stop fluid removal (what are the risks of removing too much fluid)
The literature shows that a negative fluid balance increases survival in patients with septic shock . Patients managed with a conservative fluid strategy also seem to have improved lung function, shorter duration of mechanical ventilation and intensive care stay without increasing non-pulmonary organ failure . However, any measurement in the ICU will only be of value as long as it is accurate and reproducible, and no measurement has ever improved survival, only a good protocol can do this. Vice versa a poor treatment algorithm can result in potential harm to the patient . Patients who are in the ebb or flow phase of shock have different clinical presentations and therefore different monitoring needs (targets) and different treatment goals [8, 9].
The case of a 26-year-old man admitted to the ICU after general seizures is presented. This case was presented at the 32nd annual international symposium on intensive care and emergency medicine (ISICEM) in Brussels on March 22nd and at the 2nd International Fluid Academy Day (IFAD) in Antwerp on November 17th, both meetings were held in 2012. Finally, the same case was presented at the 33rd annual ISICEM pre-congress symposium course on abdominal problems in Brussels on March 18th 2013.
A 5-item questionnaire was shown electronically to the participants. Each multiple-choice question was shown during the case presentation lecture and participants were allowed to provide their feedback via a voting system (DIF Media). This case report will present the clinical case scenario as well as the results of the voting during both aforementioned meetings.
A 26-year-old male is admitted to the intensive care unit with general seizures, syncope, non-palpable blood pressure, and a suspicion of ventricular tachycardia whilst in the Emergency Room. The emergency room physician therefore (successfully) applied a DC shock to convert him to regular sinus rhythm. Afterwards the patient was alert and cooperative and he was transferred to the ICU for mere overnight “baby-sitting”. From his previous history, we know that he has been deprived of oxygen at birth, and consequently suffered a cerebrovascular accident (CVA) with left hemiparesis and seizures (managed with triple antiepileptic therapy, carbamazepine, topiramate and lamotrigine). Because of his cognitive deficit, he normally attends a special day care institution. For the last 9 years he had also been diagnosed with idiopathic cardiomyopathy with a left ventricular ejection fraction (LVEF) of 52% (treated with an angiotensin converting enzyme inhibitor) and a mild mitral regurgitation.
Overnight in the ICU, he was initially hemodynamically stable with no further seizures. However, his need for supplemental oxygen increased from 2 liters via nasal cannula to 15 liters administered with a non-rebreathing mask. The patient was in respiratory distress with a respiratory rate of 34 breaths per minute. After failing a trial of non-invasive ventilation, he was intubated and mechanically ventilated within 24 hours of ICU admission, illustrating the dramatic chain of events. Respiratory rate was set at 24 breaths per minute and inspiratory pressures towards a tidal volume of 6ml/kg predicted body weight (PBW). Figure 1a shows the chest X-ray on admission and 1b just after intubation.
He then became hemodynamically unstable. Therefore, a transthoracic cardiac ultrasound (US) was performed (Figure 2) and the results are listed in Table 1 together with the ventilator settings and blood gas results.
Figure 2 – A2C demonstrating dilated LV and MR.
Multiple choice question 1
At this stage, the participants of the ISICEM and IFAD meetings were asked the first multiple choice question (MCQ1):
- “Taking into account the results obtained with the transthoracic cardiac ultrasound, what is your treatment of choice at this stage?”
Possible answers were:
- fluid bolus
Figure 3 shows the results of the three votings.
Based on the cardiac US findings physicians at ISICEM and iFAD seemed reluctant to fill the patient (only 6 to 13% stated to give a fluid bolus) and most of them were in favour of administrating dobutamine (39 to 64%).
The FiO2 was increased to 100% and the PEEP was set according to the low flow pressure-volume (PV) loop (as can be automatically constructed with the Draeger Evita XL ventilator). Figure 4 shows the PV loop with detection of a lower inflection point at 16 cmH2O.
During the PV loop, that also acted as a recruitment manoeuvre, his systolic blood pressure decreased to 40 mmHg, so norepinephrine was started and swiftly increased to 0.4 ug/kg/min. Dobutamine was also started at 4 ug/kg/min. Saturation remained poor at 88% and he was switched to high frequency percussive ventilation (HFPV) with the VDR4 ventilator (Percussionaire Corporation, Sandpoint, Idaho, U.S.A). A transpulmonary thermodilution PiCCO catheter (Pulsion Medical Systems, Munich, Germany) was inserted in the femoral artery at this point. The evolution of the hemodynamic parameters obtained after insertion of the PiCCO catheter together with the respiratory variables are listed in Tables 2 and 3.
CI: cardiac index (L/min.m2)
CVP: central venous pressure (mmHg)
EVLWI: extravascular lung water index (ml/kg PBW)
GEDVI: global end diastolic volume index (ml/m2)
GEF: global ejection fraction (%)
HR: heart rate (bpm)
MAP: mean arterial pressure (mmHg)
PPV: pulse pressure variation (%)
PVPI: pulmonary vascular permeability index
Table 2 – Evolution of hemodynamic parameters obtained with transpulmonary thermodilution (PiCCO).
IPAP: inspiratory positive airway pressure (cmH2O)
PEEP: positive end expiratory pressure (cmH2O)
P/F: pO2 over FiO2 ratio
RR: respiratory rate
TV: tidal volume (ml)
VDR4: high frequency percussive ventilator
Vent: type of ventilator
Table 3 – Evolution of respiratory and oxygenation parameters.
The initial hemodynamic picture showed a normal cardiac index (CI) of 3.5 L/min.m2 (normal range 3-5), a relatively low intravascular filling status with a GEDVI of 757 ml/m2 (normal range 680-800), a very low global ejection fraction GEF of 13% (normal range 25-35) but a very severe capillary leak with high extravascular lung water index (EVLWI) of 38 ml/kg predicted body weight (normal range 3-7). The high EVLWI was suggestive of hyper permeability edema in view of the high pulmonary vascular permeability index (PVPI) of 7.4 (normal range 1-2.5) .
At the same time however the patient seemed to be fluid responsive with a high pulse pressure variation (PPV) of 19% (normal range <10). Heart rate was regular at 119 beats per minute with a MAP of 65 mmHg. The CVP was still 16 mmHg. His response to a passive leg raising (PLR) maneuver was positive (15% increase in CI and MAP) confirming that he was volume responsive despite the fact that he had such bad pulmonary edema (EVLWI 38) with a critical oxygenation status (P/F ratio of 57, at IPAP of 34 cmH2O and PEEP of 15 cmH2O).
Multiple choice question 2
At this stage, the participants of the ISICEM and IFAD meetings were asked the second multiple choice question (MCQ2):
- “Taking into account the results obtained with the transpulmonary thermodilution, what is your treatment of choice at this stage?”
Possible answers were:
- fluid bolus
Figure 5 shows the results of three votings.
Again, physicians were reluctant to fill the patient initially (with only 0 to 22% indicating to give a fluid bolus). This patient had a relatively normal preload according to the volumetric preload indicator as was obtained by PiCCO (GEDVI 757 ml/m2) but a high preload according to the barometric preload indicator (CVP 16 mmHg). Measurement of bladder pressure showed a slightly increased IAP of 12 mmHg . The Surviving Sepsis Campaign Guidelines (SSCG) originally recommended that patients should be resuscitated towards a CVP range of 8-12 mmHg . The previous revision of the SSCG still advocates initial fluid management based on CVP measurements . However, using pressures to measure preload has been found to be inaccurate time and time again, particularly in patients ventilated with intermittent positive pressure ventilation (IPPV), (auto) PEEP, post cardiac surgery, obesity and those with intra-abdominal hypertension or abdominal compartment syndrome [5, 20]. Using a CVP threshold therefore may lead to over- but also under-resuscitation. Although it is re-assuring and noteworthy that the previous SSCG version does mention the effects of increased ITP and IAP on CVP:
“In mechanically ventilated patients or those with known preexisting decreased ventricular compliance, a higher target CVP of 12 to 15 mm Hg should be achieved to account for the impediment in filling. Similar consideration may be warranted in circumstances of increased abdominal pressure. Elevated CVP may also be seen with preexisting clinically significant pulmonary artery hypertension, making use of this variable untenable for judging intravascular volume status.”
Within this respect the compliance of the thorax and the abdomen are key elements in order to explain the index of transmission of a given pressure from one compartment to another :
“The use of lung-protective strategies for patients with ARDS… has been widely accepted, but the precise choice of tidal volume… may require adjustment for such factors as the plateau pressure achieved, the level of positive end-expiratory pressure chosen, the compliance of the thoracoabdominal compartment, …” .
This lead recently to the recognition of the polycompartment syndrome [21, 22]. The last version of the SSCG finally has left the CVP criterion and has introduced functional hemodynamics and passive leg raising test (PLR)[23, 24].
In the case study (dating before the publication of the big fluid trials) the patient was given small volume resuscitation with hyperhaes (Fresenius Kabi) at a dose of 4ml/kg given as a bolus over 10-15 minutes combined with 1000 ml of balanced colloids (Volulyte, 6% hydroxyethyl starch 130/0.4), following the results obtained with the transpulmonary thermodilution.
Editorial Comment: “We have to note that after the EMEA PRAC recommendations, nowadays the use of starches cannot be advocated in patients with sepsis, burns or kidney injury. Instead of hyperhaes, a hypertonic salt solution 6% can be used.”
The patient remained on a dobutamine infusion (9 ug/kg/min) and norepinephrine (0.4 ug/kg/min). The following day (day 2) his CI increased to 5.7 L/min.m2, GEDVI increased to 900 ml/m2 and EVLWI had decreased to 14 ml/kg PBW (Table 2). Despite the filling, his CVP decreased from 16 to 6 mmHg, illustrating the opposite changes between barometric and volumetric preload indices due to increased intrathoracic pressure.
This is an example of a therapeutic dilemma or conflict . A therapeutic conflict is a situation where each of the possible therapeutic decisions carries some potential harm . In high-risk patients, the decision about fluid administration should be done within the context of a therapeutic conflict. Therapeutic conflicts are the biggest challenge for protocolized cardiovascular management in anesthetized and critically ill patients. A therapeutic conflict is where our decisions can make the most difference. Although the patient had evidence of severe pulmonary edema (EVLWI 38 ml/kg PBW) the decision was made to give fluids because the PPV was high and the PLR test was positive. Also, the GEDVI was relatively low in relation to the GEF, despite the increased CVP and increased left ventricular end diastolic area (from the ultrasound) [6, 27]. Cardiac US further showed that his inferior vena cava collapsibility index (IVCCI) was almost 50% (Figure 6).
What was really important to know for this patient was the type of curve and where he was on his Frank Starling curve (Figure 7a).
Evidence shows that when the global end-diastolic volume and the right ventricular end-diastolic volume are corrected for the GEF they correlate more closely especially when compared to the change in CVP or PAOP (Figure 7b) .
Observation of the transpulmonary thermodilution curve also allowed us to get further diagnostic clues (Figure 8).
Multiple choice question 3
At this stage, the participants of the ISICEM and IFAD meetings were asked the third multiple choice question (MCQ3):
- “What is the premature hump that appeared on the transpulmonary thermodilution curve?”.
Possible answers were:
- Nothing to worry about, it is just an example of the crosstalk phenomenon
- It is related to thermal bolus mixing
- It may be an indicator of a right-to-left shunt due to pulmonary hypertension
- It is related to a wrong or false measurement technique
- I don’t know
Figure 9 shows the results of three votings.
The premature hump is evidence for a right to left shunt where an opening (foramen ovale) appears between the right and left atria. About half of the participants (41 to 61%) indicated the correct answer. Because the patient was extremely hypovolemic, the combination of positive pressure ventilation with high PEEP led to increased pulmonary vascular resistances, pulmonary hypertension and a propagation of West zone 1 conditions to zones 2 and 3. This phenomenon has been documented before [29, 30].
By late afternoon of day 2, the patient had had a drop in urine output with production of only 350 mls over the last 12 hours despite a positive cumulative fluid balance of 4 litres. He was still on dobutamine 5 ug/kg/min, and norepinephrine 0.2 ug/kg/min. Other parameters are listed in Tables 2 and 3, and can be summarized as follows: CI 5.4 L/min.m2, MAP 79 mmHg, CVP 8 mmHg, PPV 6 %, GEF 23 %, GEDVI 1080 ml/m2, EVLWI 18 ml/kg PBW, conclusive with overfilling and worsening pulmonary edema in the absence of fluid responsiveness. Respiratory function deteriorated with a P/F ratio of 205, at an IPAP of 34 cmH2O, PEEP 11 cmH2O, while FiO2 was increased from 45 to 65%. Lactate levels increased from 1.6 to 2.6 mmol/L
Multiple choice question 4
At this stage, the participants of the ISICEM and IFAD meetings were asked the fourth multiple choice question (MCQ4):
- “Taking into account the new results obtained with the transpulmonary thermodilution and the drop in urine output, what is your treatment of choice at this stage?”
Possible answers were:
- fluid bolus
Figure 10 shows the results of three votings.
The majority of participants (49 to 75%) was now in favour of administration of diuretics. Finally, the physicians fully understand the clinical situation of this patient who after the initial ebb phase of shock did not enter the flow phase spontaneously. His PEEP was increased to 18 cmH2O, along with the administration of hypertonic albumin 20%, and he was given an infusion of Lasix® (frusemide, 60mg/hr for 2 hours then followed by 10 mg/hr according to urine output). This treatment was recently referred to as PAL . PAL is one of the therapeutic options that can be used during deresuscitation . By day 3 his cardiorespiratory condition improved with a drop in EVLWI to 15 ml/kg PBW, a PVPI of 1.9 and P/F ratio of 266 (with IPAP 34 and PEEP at 18 cmH2O). Vasopressors and inotropes were titrated to norepinephrine doses of 0.11 ug/kg/min and Dobutamine at 3 ug/kg/min respectively, and he required less albumin 20% and less frusemide.
Things continued to fluctuate for the patient over the next few days but with two more episodes of frusemide infusions eventually his EVLWI came down to 8 ml/kg PBW on day eight. The patient was extubated on day 10 and left the ICU after 2 weeks. Figure 11a shows the evolution of volumetric and barometric indicators during the first week (detail of first 2 days is shown in 11b showing opposite effects on volumetric and barometric preload indicators)
CVP: central venous pressure (mmHg)
EVLWI: extravascular lung water index (ml/kg PBW)
GEDVI: global enddiastolic volume index (ml/m2)
Figure 11a – Evolution of barometric and volumetric indices during the first week of ICU stay. X-axis denotes different measurement time points, not days (corresponding to rows in Table 2). Arrows above X-axis indicate fluid administration (solid line) and diuretics (dotted line)
Figure 12 shows the daily and cumulative fluid balance.
Multiple choice question 5
At this stage, the participants of the ISICEM and IFAD meetings were asked the final multiple-choice question (MCQ5):
- “What is your opinion on a positive cumulative fluid balance in septic shock?”
Possible answers were:
- Peripheral edema may look frightening for the relatives but it is just of cosmetic concern
- A cumulative fluid balance is always a biomarker of severity of illness
- A positive fluid balance is harmful and an independent predictor for morbidity and mortality
- Fluid balance must always be positive initially for a successful resuscitation of shock
- I don’t care
Figure 13 shows the results of three voting:
It was re-assuring that the majority of participants (49 to 75%) were convinced that a positive cumulative fluid balance is indeed harmful.
In fact there is strong evidence to support conservative late fluid management in patients with septic shock, once the initial resuscitation is completed . Hospital mortality was reduced in those patients who received adequate fluid resuscitation initially followed by conservative post resuscitation fluid management (defined as having 2 consecutive negative daily fluid balances within the first 7 days of ICU stay). In a meta-analysis of 47 studies that included 19902 patients, the mean cumulative fluid balance after 1 week was much lower in survivors than non survivors: 2449 ml vs 6983 ml [9, 32].
Fluid Overload; An integrated approach.
Patients don’t die from anasarca (extreme edema), they die from multi-organ failure, and different organs need varying amounts of fluids to function. For example, lungs prefer to be dry but the liver cannot function if it is too dry. However when there is clinical evidence of capillary leak with peripheral edema then there will also be end-organ edema resulting in end-organ dysfunction, potentially leading to multiple organ dysfunction syndrome .
There are three phases or ‘hits’ a body takes when exposed to an inflammatory insult which includes trauma, infection, burns, sepsis or bleeding. This is summarized in Table 4.
Recent evidence showed that the use of PAL treatment, combining PEEP with hypertonic albumin 20% and diuretics to initiate the flow phase, (as we did in our patient), decreased EVLWI, IAP and daily and cumulative fluid balance, duration of mechanical ventilation and increased P/F ratio and survival in 57 patients with ALI compared to 57 matched controls . PAL works as follows: the PEEP moves fluids from the alveoli into the interstitium (IS), thereby increasing interstitial hydrostatic pressure and decreasing interstitial oncotic pressure and moving IS fluids towards the capillaries. The hyperoncotic albumin 20% increases the intravascular oncotic pressure thereby removing fluids from the interstitium into the capillaries and finally the frusemide (Lasix®) helps to remove the excess fluids from the patient.
This patient developed shock within 18 hours of ICU admission; the dynamic evolution is presented. Despite initial normal, (and thus adequate) filling pressures, further fluid resuscitation was needed to overcome the ebb phase (this was guided by functional hemodynamic parameters and volumetric preload indices in combination with cardiac ultrasound). Diuretics were initiated after 24 hours to help the patient to transgress to the flow phase because of respiratory failure due to capillary leak as evidenced by increased extravascular lung water. It is interesting to see from the voting that based on barometric preload indicators many physicians were reluctant to start initial fluid resuscitation, this became clear once volumetric monitoring was performed with transpulmonary thermodillution. This case nicely demonstrates the biphasic clinical course from ebb to flow phase during shock as well as the inability of traditional filling pressures to guide us through these different phases. It also provides answers to the four crucial questions that need to be solved in order not to do any harm to the patient.
It is important to know and understand:
- When to start giving fluids (low GEF/GEDVI, high PPV and positive PLR, increased lactate)
- When to stop giving fluids (high GEF/GEDVI, low PPV, negative PLR, normalized lactate)
- When to start removing fluids (high EVLWI, high PVPI, raised IAP, low APP defined as MAP minus IAP, positive cumulative fluid balance)
- When to stop fluid removal (low ICG-PDR, low APP, low ScvO2, neutral cumulative fluid balance)
However, one must realize that the above-mentioned thresholds are moving targets but also with moving goals, (from early adequate goal directed therapy, over late conservative fluid management towards late goal directed fluid removal). And above all, one must always bear in mind that unnecessary fluid loading may be harmful. If the patient does not need fluids, don’t give them, and remember that the best fluid may be the one that has not been given to the patient…! Finally, it is about time that fluids are considered as drugs, with indications, contra-indications and possible adverse effects .
**It is essential to give the right fluid at the right time in the right way, and to use appropriate monitoring modalities correctly.**
As you can see clearly….FLUIDS ARE DRUGS!
So…that’s a taster of 3 more to come soon. Again, many thanks to Manu for all of his hard work and dedication.
JW July 2017
Manu LNG Malbrain1,2
1) From the Department of ICU and High Care Burn Unit, Ziekenhuis Netwerk Antwerpen, ZNA Stuivenberg
2) From the Department of Intensive Care medicine, University Hospital Brussels (UZB)
Prof. Dr. Manu L.N.G. Malbrain, MD, PhD
ICU and High Care Burn Unit Director
Ziekenhuis Netwerk Antwerpen,
Lange Beeldekensstraat 267
Tel: +32 3 217 7399
Fax: +32 3 217 7574
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