Side effects of hypothermia

K.H. Polderman, internist/intensivistUniversity medical center Utrecht, The Netherlands

Sicily, October 19TH 2006

Factors determining the success of cooling:(in CPR) Presence and quality of CPR (by bystanders, ambulance staff, ER staff etc.);Organisational factorsSpeed of coolingDuration of cooling?(in TBI): ICP guidedSpeed of re-warming(In TBI/SAH): Response to rebound intracranial hypertensionOther (“general”) ICU treatment!!

Factors determining the success of cooling:

So, are we doing a good job:In terms of awareness by physicians?In terms of awareness by the general public?

Factors determining the success of cooling:

So, are we doing a good job:In terms of awareness by physicians?In terms of awareness by the general public?

Well, let’s look what we can learn from:

The movies!!

James Bonds’ approach to hypothermia & resuscitation:

Evaluating James Bonds’ performance: Resuscitation techniques:

Resuscitation techniques (if judged by intensive are .or ATLS standards)☺Effectiveness ☺Patient selection

Perhaps somewhat questionable relationship with .patient from an ethical viewpoint

Use of induced hypothermia:☺Awareness and use of hypothermia’s neuroprotective

.effects

Re-warming techniques

But, on a more serious note:How can we do better?

Factors determining the success of cooling:Awareness of physiology of coolingAwareness of potential side effects

Although we’ve seen yesterday that hypothermia can be neuroprotective, and probably cardioprotective…..

Its use is NOT risk-free!!There are serious There are serious potential side effects of potential side effects of which we should take which we should take into account!into account!

Hypothermia has a number of significant pitfalls!

Hypothermia has a number of significant pitfalls!

(although, as I will show, these are well manageable with good intensive care)

Firstly:Firstly: We should We should realize that realize that Everything!!Everything!!changes when you changes when you induce induce hypothermia in hypothermia in your patient.your patient.

Polderman KH. Intensive Care Med 2004;30:757-69

Metabolism

30-35oC ↓ Oxygen consumption

↓ CO2 production

↓ Metabolism

↑ Fat metabolism: ⇒ ↑ Glycerol, free fatty acids, ketonic acids, lactate; metabolic acidosis

≤35oC ↓ Insulin sensitivity ↓ insulin secretion

Metabolism

30-35oC ↓ Oxygen consumption

↓ CO2 production

↓ Metabolism

↑ Fat metabolism: ⇒ ↑ Glycerol, free fatty acids, ketonic acids, lactate; metabolic acidosis

≤35oC ↓ Insulin sensitivity ↓ insulin secretion

0m

l/100

g/m

in60

0m

l/100

g/m

in60

Acute head injury (6 hrs post impact)Areas in red show regions with rCBF < 20 ml/100g/min)

PaCO2: 25 mmHg (3.3 kPa)PaCO2: 38 mmHG (5.0 kPa)

Coles JP et al. Effect of hyperventilation on cerebral blood flow in traumatic head injury: clinicalrelevance and monitoring correlates. Crit Care Med 2002;30:1950-9.

Some lab measurements are affected by temperature

Coagulation parameters: PTT, APTT

Blood gas analysis: pH, PO2, PCO2

Mixed venous saturation:

Cardiovascular≤36->35oC Tachycardia

≤35oC Bradycardia

≤34oC Slight increase in blood pressure (average 10 mmHg)

≤32oC Mild arrhythmias in some patients

≤33oC EKG changes: increased PR-interval, widening of QRS-complex, increased QT interval.

≤28-30oC ↑↑ Risk of tachyarrhythmia’s, beginning with atrial fibrillation

≤35oC ↑ CVP and ↓ CO

≤35oC ↑ or = mixed venous saturation

Inflammation & immune function

≤35oC Impaired neutrophil and macrophage function; suppression of pro-inflammatory mediator release; ⇒ increased risk of infection (mainly pneumonia & wound infections)

Inflammation & immune function

≤35oC Impaired neutrophil and macrophage function; suppression of pro-inflammatory mediator release; ⇒ increased risk of infection (mainly pneumonia & wound infections)

≤35oC ↓ Platelet count, impaired platelet function, impaired coagulation cascade

≤33oC ↓ White blood cell count, impaired leucocytefunction

Pharmacokinetics≤35oC Altered clearance of various medications

(data available for muscle paralyzers, propofol, fentanyl, phenytoin, pentobarbital, verapamil, propanolol and volatile anaesthetics (reduced clearance). In all likelihood this applies to many other types of medication, though effect of temp on clearance has not been studied for many drugs.

Gastro-intestinal function≤35oC Impaired bowel function/subileus, mild

pancreatitis (occurs very frequently!) ↑ liver enzymes

Gastro-intestinal function≤35oC Impaired bowel function/subileus, mild

pancreatitis (occurs very frequently!) ↑ liver enzymes

Renal function

≤35oC ↑Diuresis, tubular dysfunction, electrolyte loss & electrolyte disorders

Polderman KH et al, J Neurosurg 2001;94:697-705

So what? why should we care about magnesium? Hypomagnesaemia is associated with:

Vasospasms, including spasms of coronary and cerebral arteriesIncreased risk of reperfusion injuryInsulin resistanceAdverse outcome in the ICU and general ward In animal experiments and clinical studies magnesium levels decrease after brain injuryAnd, in animal experiments:

Low Mg is associated with more extensive brain injuryAdministration of Mg before or after experimental brain injury decreases the extent of neurological damage, reducesthe loss of cortical cells and mitigates secondary injuryMagnesium reduces reperfusion injury

Vink, Front Biosci 2000;5:656-65; Bareyre et al, J Neurotrauma 2000;17:1029-39; Polderman et al, Crit Care Med 2000;28:2022-25; Nadler JL, Lancet 1998; 352:391-6; Hearse et al, Cardiovasc Res 1992; 26:101-8; Polderman et al, Intensive Care Med 2003; 29:1202-03

Physiologic attempts to increase temperature:

30-35oC Generation of heat: shivering, peripheral vasoconstriction, etc.

30-33oC ‘Hibernation’: shivering ceases, marked decrease in rate of metabolism.

“Shivering is very dangerous; it increases oxygen consumption by up to 400%, increasing the risk of hypoxic brain injury”.

“Shivering is very dangerous; it increases oxygen consumption by up to 400%, increasing the risk of hypoxic brain injury”. Incorrect:

“Shivering is very dangerous; it increases oxygen consumption by up to 400%, increasing the risk of hypoxic brain injury”. Incorrect:Shivering can lead to increases in oxygen consumption of between 40% and 100% (not 400%).

(This is certainly an undesirable effect in patients with neurological and/or post-anoxic injury; but in ventilated and sufficiently sedated patients it is less of a problem, as these patients will have sufficient oxygen supplies and no work of breathing!)

Shivering can be counteracted by administration of (preferably) opiates, sedatives, or brief-acting paralyzing drugs.

Sedation and anaesthesia also increase peripheral blood flow, thereby increasing transfer of heat from the core to the periphery.

Paralysis is usually not necessary! Certainly not once target temperature has been reached.!

Matsukawa T et al. Heat flow and distribution during induction of general anesthesia. Anesthesiology 1995; 82:662-73. Frank SM et al. Multivariate determinates of early postoperative oxygen consumption: the effects of shivering, core temperature, and gender. Anesthesiology 1995; 83:241-49. Horvath SM et al. Metabolic cost of shivering. J Appl Physiol 1956; 8: 595-602

Endocrine parameters:≤35.5oC ↑ Epinephrin and norepinephrin

≤33oC ↑ Cortisol

Neurological function:

≤30-31oC ↓ Consciousness, lethargy, coma.

Do we all need to be “ER doctors”to use hypothermia effectively?

Polderman KH. Intensive Care Med 2004;30:757-69Polderman KH, Yearbook Intensive Care & Emergency Med 2004;30: 830-843

NO!

Do we all need to be “ER doctors”to use hypothermia effectively?

The “do’s” in induced hypothermia:1. Avoid hypovolaemia: use cold fluids for induction!2. Avoid electrolyte disorders: frequent measurements,

liberal supplementation in most patients (especially of Mg2+)3. Avoid hyperglycaemia: use intensive insulin therapy4. Avoid infections: consider antibiotic prophylaxis (SDD),

intensive bed sore prevention/repositioning, wound care, etc5. Appropriate sedation & analgesia!!! Protective effects of

hypothermia may be lost if patients are not properly sedated.

Polderman KH. Crit Care 2006 (in press)

Thoresen M et al. Pediatr Res 2001;50:405– 411.

Thoresen M et al. Ann Neurol 2003;53:65–72.

So, the “do’s” in induced hypothermia:1. Avoid hypovolaemia: use cold fluids for induction!2. Avoid electrolyte disorders: frequent measurements,

liberal supplementation in most patients (especially of Mg2+)3. Avoid hyperglycaemia: use intensive insulin therapy4. Avoid infections: consider antibiotic prophylaxis (SDD),

intensive bed sore prevention/repositioning, wound care, etc5. Appropriate sedation & analgesia!!! Protective effects of

hypothermia may be lost if patients are not properly sedated. Anesthesia/sedation also increase the peripheral blood flow, thereby increasing transfer of heat from the core to the periphery and facilitating cooling.

6. Adjust ventilator settings: Hypothermia decreases CO2production & oxygen consumption.

Polderman KH. Crit Care 2006 (in press)

So, the “do’s” in induced hypothermia:1. Avoid hypovolaemia: use cold fluids for induction!2. Avoid electrolyte disorders: frequent measurements,

liberal supplementation in most patients (especially of Mg2+)3. Avoid hyperglycaemia: use intensive insulin therapy4. Avoid infections: consider antibiotic prophylaxis (SDD),

intensive bed sore prevention/repositioning, wound care, etc5. Appropriate sedation & analgesia!!! Effects may be lost if

patients are not properly sedated.6. Adjust ventilator settings: Hypothermia decreases CO2

production & oxygen consumption. And remember, some lab measurements are affected by hypothermia!

Polderman KH. Crit Care 2006 (in press)

So, the “do’s” in induced hypothermia:1. Avoid hypovolaemia2. Avoid electrolyte disorders3. Avoid hyperglycaemia 4. Avoid infections 5. Appropriate sedation& analgesia

Polderman KH. Crit Care 2006 (in press)

6. Adjust ventilator settings7. Adjust feeding rate (metabolism decreases by 7%-10% per

oC decrease in temp; so decrease feed by ±40%)8. Realize that drug clearance may change; consider slowly

decreasing drug dosage during maintenance phase9. Implement an effective anti-bedsore protocol. Risk of

bedsores in increased because of hypothermia-induced peripheral vasoconstriction, anti-inflammatory effects of hypothermia, and immobilisation of the patient (sedation, paralysis)

So, the “do’s” in induced hypothermia:1. Avoid hypovolaemia2. Avoid electrolyte disorders3. Avoid hyperglycaemia 4. Avoid infections 5. Appropriate sedation& analgesia6. Adjust ventilator settings7. Adjust feeding rate8. Realize that drug clearance may change9. Implement an effective anti-bedsore protocol 10. The “other” basics!! (apart from appropriate sedation and

intensive insulin therapy): goal-directed therapy, ventilation with low TV, good (protocolised) care of central venous catheters, hand washing protocols, etc.Provide a good general level of intensive care!

Polderman KH. Crit Care 2006 (in press)

What about the “dont’s”?1. Don’t overshoot the mark; never let core temperature fall

below 30oC (because of risk of arrhythmia’s).2. Don’t “overtreat”! Eg: bradycardia, mild metabolic acidosis,

slight rise in lactate levels are normal consequences of hypothermia.

3. Don’t use long-term paralysis! Even in the induction phase muscle relaxants are usually unnecessary, and will mask inadequate sedation. They have adverse long-term consequences (critical illness polyneuromyopathy) especially after prolonged administration. Use opiates/sedation, or only brief-acting paralyzing agents!

4. Don’t be (overly) afraid of shivering! Can be counteracted by administration of (preferably) opiates and/or sedatives.

5. Don’t re-warm too quickly!

Polderman KH. Crit Care 2006 (in press)

What about the “dont’s”?1. Don’t overshoot the mark; never let core temperature fall

below 30oC (because of risk of arrhythmia’s).2. Don’t “overtreat”! Eg: bradycardia, mild metabolic acidosis,

slight rise in lactate levels are normal consequences of hypothermia.

3. Don’t use long-term paralysis! Even in the induction phase muscle relaxants are usually unnecessary, and will mask inadequate sedation. They have adverse long-term consequences (critical illness polyneuromyopathy) especially after prolonged administration. Use opiates/sedation, or only brief-acting paralyzing agents!

4. Don’t be (overly) afraid of shivering! Can be counteracted by administration of (preferably) opiates and/or sedatives.

5. Don’t re-warm too quickly!6. When using ice-packs as an (accessory) cooling method:

avoid excessively lengthy exposure & pressure

The good news:

Most of hypothermia’s side effects can be prevented or controlled!

Practical aspects ofinducing hypothermia

Alsius

Cold fluid infusion:Two studies in patients with CPR (total: 43 patients) used refrigerated Ringers lactate to induce hypothermia, and concluded that this was safe and effective

(limitations: metabolic effects not studied; CVP not measured)Similar findings in small study in 9 healthy volunteersWe performed a similar study in 134 patients with various types of neurological injury

(mostly post-anoxic encephalopathy, subarachnoidhaemorrhage, and traumatic brain injury)Hypothermia induced through infusion of refrigerated (4oC) saline or geloplasma, average 2320 ± 890 ml within 45 minutes.

Bernard et al, Rescuscitation 2003;56:9-13; Virkkunen et al., Resuscitation 2004; 62:299-302; Rijnsburger et al., Intensive Care Med 2004 30:Suppl 1 abstr 475; Polderman et al., Critical Care Med 2005; 33:2744-51.

Polderman et al. Critical Care Med 2005; 33:2744-51.

Results:Core temperatures decreased from 36.9 ± 1.9 to 34.1 ± 1.3oC at t=30 minutes and to 32.9 ±0.9oC at t=60 minutes (target temperatures: 32 or 33oC). No complicationsSmall rise in CVP, improvement in various haemodynamic parameters (blood pressure, urine production etc)No ventilatory problemsChlorine levels increased by 1.8 mmol; no acidosis

Polderman et al. Critical Care Med (in press); Rijnsburger et al., Intensive Care Med 2004 30:Suppl 1 abstr 475Polderman et al. Critical Care Med 2005; 33:2744-51.

Combined surface & core coolingPotential advantages

Less difference in temperature ⇒less risk of overshoot, less degree of overshootMuch faster cooling ratesPatients with neurological injuries almost always require significant fluid loading in the first period after admission; In cardiac arrest patients this is usually caused by a SIRS-like reperfusion reaction.

The solution: In induction phase: combine surface cooling

with core cooling using infusion of cold fluids

This shifts the perspective:Reliable temperature control duringmaintenance phase;Controlled (slow!) re-warmingMaintaining hypothermia over longer periods of time (ICP control, fever control!!)Controlling the side effects of hypothermia!

InfectionsMetabolic disorders (glucose, electrolytes)Bed sores

Maintenance phase

Re-warming phase

Re-warming phase

20 hours, 0,20oC/hr

Which target temperature?

--34°C

--32°C

36°C--

30°C--

Safe range Therapeutic Window?

Slightly higher risk

28°C

Too low will increase the risk of adverse events and may negate (some of) the benefits of cooling

High risk; Re-warm!

Temperature monitoring sites

PA catheterOesophagusRectalBladderTympanic

3 options:All patients with ROSC after cardiac arrest who are not following verbal commands?Only witnessed arrestOnly VF/VT and age 18-75 (HACA/Bernard study inclusion criteria)

Patient selection

3 options:All patients with ROSC after cardiac arrest who are not following verbal commands!Only witnessed arrestOnly VF/VT and age 18-75 (HACA/Bernard study inclusion criteria)

Patient selection

How long to cool?

12 hours?24 hours?Longer???

Published data not clear on this issue

12-24 hour period chosen in studies to minimize side effects; longer cooling periods used in neonatal studies

Understanding of mechanisms will help define this parameter in future work

Counter-indications?Persistent hypotension?Arrhythmia’s?Active bleeding? Pregnancy? Severe pre-admission morbidity?High age?

Counter-indications?Persistent hypotension? NoArrhythmia’s? No (provided temp stays >30oC)

Active bleeding? PerhapsPregnancy? No???Severe pre-admission morbidity? ??High age? No

If the patient is worth admitting to the ICU he/she should receive hypothermia treatment

Conclusions

Hypothermia can help us improve outcome in patients with neurological injuries….

(and it will be easier than you think!!)

BUT it isvery important to prevent side effects!!

Polderman KH. Intensive Care Med 2004;30:757-69Polderman KH, Yearbook Intensive Care & Emergency Med 2004;30: 830-843

The do’s:1. Avoid hypovolaemia2. Avoid electrolyte disorders3. Avoid hyperglycaemia 4. Avoid infections 5. Appropriate sedation& analgesia6. Adjust ventilator settings7. Adjust feeding rate8. Realize that drug clearance may change9. Implement an effective anti-bedsore protocol 10. The “other” basics!! (apart from appropriate sedation and

intensive insulin therapy): goal-directed therapy, ventilation with low TV, good (protocolised) care of central venous catheters, hand washing protocols, etc.Provide a good general level of intensive care!

Polderman KH. Crit Care 2006 (in press)

The dont’s….1. Don’t overshoot the mark; never let core temperature fall

below 30oC (because of risk of arrhythmia’s).2. Don’t “overtreat”! Eg: bradycardia, mild metabolic acidosis,

slight rise in lactate levels are normal consequences of hypothermia.

3. Don’t use long-term paralysis! Even in the induction phase muscle relaxants are usually unnecessary, and will mask inadequate sedation. They have adverse long-term consequences (critical illness polyneuromyopathy) especially after prolonged administration. Use opiates/sedation, or only brief-acting paralyzing agents!

4. Don’t be (overly) afraid of shivering! Can be counteracted by administration of (preferably) opiates and/or sedatives.

5. Don’t re-warm too quickly!6. When using ice-packs as an (accessory) cooling method:

avoid excessively lengthy exposure & pressure

I would like to provide my take-home message in the form of a movie:

I would like to provide my take-home message in the form of a movie:

Take-home message:☺Hypothermia is a highly promising treatment

that, if used appropriately, can lead to excellent resultsBut, if applied improperly, the side effects

can be very severe, and even negate any positive effects that had been realized up to that point.

Take-home message:

☺Awareness of these risks and of theunderlying physiology, and taking proper precautions to avoid these problems, will be the key to success.

☺Hypothermia is a highly promising treatment that, if used appropriately, can lead to excellent resultsBut, if applied improperly, the side effects

can be very severe, and even negate any positive effects that had been realized up to that point.

So, with that I thank you for your attention….

..I wish you lots of fun

with hypothermia..

☺And keep your eye on the temperature!And keep your eye on the temperature!